Active Signal Processing Personal Health Signal Receivers

ABSTRACT

The invention provides a receiver associated with a body, e.g., located inside or within close proximity to a body, configured to receive and decode a signal from an in vivo transmitter which located inside the body. Signal receivers of the invention provide for accurate signal decoding of a low-level signal, even in the presence of significant noise, using a small-scale chip, e.g., where the chip consumes very low power. Also provided are systems that include the receivers, as well as methods of using the same.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.12/515,527 filed Mar. 3, 2010, which is a 371 National Phase Applicationof PCT/US2007/024225 filed Nov. 19, 2007, which claims the benefit ofU.S. Provisional Patent Application Ser. No. 60/866,581 filed Nov. 20,2006 and U.S. Provisional Patent Application Ser. No. 60/945,251 filedJun. 20, 2007; the disclosures of which applications are hereinincorporated by reference.

INTRODUCTION

Communications play an extremely important role in today's world.Computers, telephones, audio and multimedia players, medical devices,scientific equipment, and other technology both provide and rely onvarious types of communications.

Communications, however, are susceptible to errors. In particular, noisytransmission environments distort and corrupt communication data. Suchenvironments include the human body, deep space transmissions, highspeed transmissions, and high compression storage media. Additionally,devices err in signal generation and measurement related to thecommunication data.

As such, there is a continued need for improved communication devicesand systems. Of particular interest is the development of communicationsdevices and systems that can be employed to reliably communicateinformation from an in vivo location.

SUMMARY

The invention provides a receiver associated with a body, e.g., locatedinside or within close proximity to a body, configured to receive anddecode a signal from an in vivo transmitter which is located inside thebody. Signal receivers of the invention provide for accurate signaldecoding of a low-level signal, even in the presence of significantnoise, using a small-scale chip, e.g., where the chip consumes very lowpower. Also provided are systems that include the receivers, as well asmethods of using the same.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows a high-level block diagram of one embodiment of the in-vivotransmission decoder.

FIG. 2 shows a block diagram of one embodiment of the automatic gaincontrol and Costas loop blocks of the in-vivo transmission decoder.

FIG. 3 shows a block diagram of one embodiment of the automatic gaincontrol block of the in-vivo transmission decoder.

FIG. 4 shows a block diagram of one embodiment of the Costas loop blockof the in-vivo transmission decoder.

FIG. 5 shows a block diagram of one embodiment of the symbol recoveryblock of the in-vivo transmission decoder.

FIGS. 6A to 6C provide circuit diagrams according to certain embodimentsof the invention.

FIG. 7 is a system view of a communication environment including adecoder module, according to one embodiment.

FIG. 8A is an illustration of unencoded data, according to oneembodiment.

FIG. 8B is an illustration of encoded data, according to one embodiment.

FIG. 8C is an illustration of transmission symbols, according to oneembodiment.

FIG. 9A is an illustration of measured signals, according to oneembodiment.

FIG. 9B is another illustration of transmission symbols, according toone embodiment.

FIG. 9C is an illustration of hard code decision values, according toone embodiment.

FIG. 9D is an illustration of adjusted measured signals, according toone embodiment.

FIG. 10 is a flowchart of a method associated with decoding, accordingto one embodiment.

FIG. 11 is a schematic of a communication environment including acommunications decoder, according to one embodiment.

DETAILED DESCRIPTION

The invention provides a receiver associated with a body, e.g., locatedinside or within close proximity to a body, configured to receive anddecode a signal from an in vivo transmitter which is located inside thebody. Signal receivers of the invention provide for accurate signaldecoding of a low-level signal, even in the presence of significantnoise, using a small-scale chip, e.g., where the chip consumes very lowpower. Also provided are systems that include the receivers, as well asmethods of using the same.

In further describing the invention in greater detail, embodiments ofthe signal receivers are reviewed first in greater detail, followed by adiscussion of systems that include the subject signal receivers, methodsof using the subject signal receivers and systems and variousillustrative applications in which the signal receivers, systems andmethods find use. Also reviewed in greater detail below are kits thatinclude the subject signal receivers.

Signal Receivers-Overview

Aspects of the invention include signal receivers configured to receivean encoded signal produced by an in vivo transmitter. Signal receiversof the invention are configured to decode an encoded signal receivedfrom an in vivo transmitter. The receivers are configured to decode theencoded signal in a low signal to noise ratio (SNR) environment, e.g.,where there may be substantial noise in addition to the signal ofinterest, e.g., an environment having an SNR of 7.7 dB or less. Thereceivers are further configured to decode the encoded signal withsubstantially no error. In certain embodiments, the signal receiver hasa high coding gain, e.g., a coding gain ranging from 6 dB to 12 dB, suchas a coding gain ranging from 8 dB to 10 dB, including a coding gain of9 dB. The signal receivers of the invention decode encoded signals withsubstantially no error, e.g., with 10% error or less.

Signal receivers of embodiments of the invention are configured toreceive an encoded signal from a pharma-informatics enabledpharmaceutical composition (e.g., as described in PCT application SerialNo. US2006/016370; the disclosure of which is specifically incorporatedherein by reference), an ingestible event marker (e.g., as described inprovisional application Ser. No. 60/949,223, the disclosure of which isherein incorporated by reference), a smart parenteral device (e.g., asdescribed in PCT/US2007/15547; the disclosure of which is hereinincorporated by reference, or analogous device.

In certain embodiments, the receiver is configured to receive a signalconductively from another component, e.g., identifier of apharmaceutical, a parenteral delivery device, an ingestible eventmarker, etc., such that the two components use the body of the patientas a communication medium. To employ the body as a conduction medium forthe signal, the body of the patient is used as a communication medium.As such, the signal that is transferred between identifier and thereceiver travels through the body, and requires the body as theconduction medium.

Mobile embodiments of the signal receiver include ones that are sized tobe stably associated with a living subject in a manner that does notsubstantially impact movement of said living subject. As such,embodiments of the signal receiver have dimensions that, when employedwith a subject, such as a human subject, will not cause the subject toexperience any difference in its ability to move. As such, in theseembodiments, the receiver is dimensioned such that its size does nothinder the ability of the subject to physically move. In certainembodiments, the signal receiver has a small size, where in certainembodiments, the signal receiver occupies a volume of space of about 5cm³ or less, such as about 3 cm³ or less, including about 1 cm³ or less.In certain embodiments, the signal receiver has a chip size limitranging from 10 mm² to 2 cm².

The signal receivers of interest include both external and implantablesignal receivers. In external embodiments, the signal receiver is exvivo, by which is meant that the receiver is present outside of the bodyduring use.

Where the signal receivers are external, they may be configured in anyconvenient manner, where in certain embodiments they are configured tobe associated with a desirable skin location. As such, in certainembodiments the external signal receivers are configured to be contactedwith a topical skin location of a subject. Configurations of interestinclude, but are not limited to: patches, wrist bands, belts, etc. Forinstance, a watch or belt worn externally and equipped with suitablereceiving electrodes can be used as signal receivers in accordance withone embodiment of the present invention. The signal receivers mayprovide a further communication path via which collected data can beextracted by a patient or health care practitioner. For instance, animplanted collector may include conventional RF circuitry (operating,e.g., in the 405-MHz medical device band) with which a practitioner cancommunicate, e.g., using a data retrieval device, such as a wand as isknown in the art. Where the signal receiver includes an externalcomponent, that component may have output devices for providing, e.g.,audio and/or visual feedback; examples include audible alarms, LEDs,display screens, or the like. The external component may also include aninterface port via which the component can be connected to a computerfor reading out data stored therein. By further example, it could bepositioned by a harness that is worn outside the body and has one ormore electrodes that attach to the skin at different locations.

In certain external embodiments, the receiver is configured to be incontact with or associated with a patient only temporarily, i.e.,transiently, for example while the pill, ingestible marker, etc., isactually being ingested. For example, the receiver may be configured asan external device having two finger electrodes or handgrips. Uponingestion of a pharma informatics enabled pill, the patient touches theelectrodes or grabs the handgrips completely a conductive circuit withthe receiver. Upon emission of the signal from the pill, e.g., when thepill dissolves in the stomach, the signal emitted by the identifier ofthe pill is picked up by the receiver. Where the signal receiverincludes an external component, that component may have output devicesfor providing, e.g., audio and/or visual feedback; examples includeaudible alarms, LEDs, display screens, or the like. The externalcomponent may also include an interface port via which the component canbe connected to a computer for reading out data stored therein.

In certain embodiments, the external signal receiver includesminiaturized electronics which are integrated with the electrodes toform a band-aid style patch with electrodes that when applied, contactthe skin, and a battery and electronics contained in that package. Thebandaid style patch may be configured to be positioned on a desirabletarget skin site of the subject, e.g., on the chest, back, side of thetorso, etc. In these embodiments, the bandaid circuitry may beconfigured to receive signals from devices inside of the subject, e.g.,from an identifier of a pharma-informatics enabled pharmaceuticalcomposition, and then relay this information to an external processingdevice, e.g., a PDA, smartphone, etc., as described in greater detailelsewhere. Bandaid style devices that may be readily adapted for use inthe present systems include, but are not limited to: those described inU.S. Pat. No. 6,315,719 and the like, the disclosures of which areherein incorporated by reference.

In certain embodiments, the signal receiver (i.e., signal detectioncomponent) is an implantable component. By implantable is meant that thesignal receiver is designed, i.e., configured, for implantation into asubject, e.g., on a semi-permanent or permanent basis. In theseembodiments, the signal receiver is in vivo during use. By implantableis meant that the receivers are configured to maintain functionalitywhen present in a physiological environment, including a high salt, highhumidity environment found inside of a body, for 2 or more days, such asabout 1 week or longer, about 4 weeks or longer, about 6 months orlonger, about 1 year or longer, e.g., about 5 years or longer. Incertain embodiments, the implantable circuits are configured to maintainfunctionality when implanted at a physiological site for a periodranging from about 1 to about 80 years or longer, such as from about 5to about 70 years or longer, and including for a period ranging fromabout 10 to about 50 years or longer.

For implantable embodiments, the signal receiver may have any convenientshape, including but not limited to: capsule-shaped, disc-shaped, etc.One way we would achieve the small size is by including a rechargeablebattery. Because this is not a life-support device, it is a sensingdevice, it could have a natural life of 2 weeks, and rechargeautomatically off of coils in the patient's bed so that it would beconstantly recharging. The signal receiver may be configured to beplaced in a number of different locations, e.g., the abdomen, small ofthe back, shoulder (e.g., where implantable pulse generators are placed)etc.

In certain implantable embodiments, the signal receiver is a stand alonedevice, in that it is not physically connected to any other type ofimplantable device. In yet other embodiments, the signal receiver may bephysically coupled to a second implantable device, e.g., a device whichserves as a platform for one or more physiological sensors, where thedevice may be a lead, such as a cardiovascular lead, where in certain ofthese embodiments the cardiovascular lead includes one or more distinctphysiological sensors, e.g., where the lead is a multi-sensor lead(MSL). Implantable devices of interest further include, but are notlimited to: implantable pulse generators (e.g., ICDs), neurostimulatordevices, implantable loop recorders, etc.

Signal receivers of the invention include a signal receiver elementwhich serves to receive the identifier emitted signal of interest. Thesignal receiver may include a variety of different types of signalreceiver elements, where the nature of the receiver element necessarilyvaries depending on the nature of the signal produced by the signalgeneration element. In certain embodiments, the signal receiver mayinclude one or more electrodes for detecting signal emitted by thesignal generation element. In certain embodiments, the receiver devicewill be provided with two electrodes that are dispersed at somedistance. This distance allows the electrodes to detect a differentialvoltage. The distance may vary, and in certain embodiments ranges fromabout 0.1 to about 5 cm, such as from about 0.5 to about 2.5 cm, e.g.,about 1 cm. In certain embodiments, the first electrode is in contactwith an electrically conductive body element, e.g., blood, and thesecond electrode is in contact with an electrically insulative bodyelement relative to said conductive body element, e.g., adipose tissue(fat). In an alternative embodiment, a receiver that utilizes a singleelectrode is employed. In certain embodiments, the signal detectioncomponent may include one or more coils for detecting signal emitted bythe signal generation element. In certain embodiments, the signaldetection component includes an acoustic detection element for detectingsignal emitted by the signal generation element.

A signal receiver may handle received data in various ways. In someembodiments, the signal receiver simply retransmits the data to anexternal device (e.g., using conventional RF communication). In otherembodiments, the signal receiver processes the received data todetermine whether to take some action such as operating an effector thatis under its control, activating a visible or audible alarm,transmitting a control signal to an effector located elsewhere in thebody, or the like. In still other embodiments, the signal receiverstores the received data for subsequent retransmission to an externaldevice or for use in processing of subsequent data (e.g., detecting achange in some parameter over time). The signal receivers may performany combination of these and/or other operations using received data.

In certain embodiments, the data that is recorded on the data storageelement includes at least one of, if not all of, time, date, and anidentifier (e.g., global unique serial no.) of each compositionadministered to a patient, where the identifier may be the common nameof the composition or a coded version thereof. The data recorded on thedata storage element of the receiver may further include medical recordinformation of the subject with which the receiver is associated, e.g.,identifying information, such as but not limited to: name, age,treatment record, etc. In certain embodiments, the data of interestincludes hemodynamic measurements. In certain embodiments, the data ofinterest includes cardiac tissue properties. In certain embodiments, thedata of interest includes pressure or volume measurements, temperature,activity, respiration rate, pH, etc.

As summarized above, the signal receivers can be configured to have avery small size. In certain embodiments, the desired functionality ofthe signal receiver is achieved with one or more integrated circuits anda battery. Aspects of the invention include receivers that have at leasta receiver element, e.g., the form of one or more electrodes (such astwo spaced apart electrodes) and a power generation element, e.g., abattery, where the battery may be rechargeable, etc., as mentionedabove. As such, in certain embodiments the power generation element isconverted to receive power wirelessly from an external location.

Additional elements that may be present in the signal receiver include,but are not limited to: a signal demodulator, e.g., for decoding thesignal emitted from the pharma-informatics enabled identifier; a signaltransmitter, e.g., for sending a signal from the signal receiver to anexternal location; a data storage element, e.g., for storing dataregarding a received signal, physiological parameter data, medicalrecord data, etc.; a clock element, e.g., for associating a specifictime with an event, such as receipt of a signal; a pre-amplifier; amicroprocessor, e.g., for coordinating one or more of the differentfunctionalities of the signal receiver.

Aspects of implantable versions of the signal receiver will have abiologically compatible enclosure, two or more sense electrodes, a powersource, which could either be a primary cell or rechargeable battery, orone that is powered by broadcast inductively to a coil. The signalreceiver may also have circuitry consisting of: a demodulator to decodethe transmitted signal, some storage to record events, a clock, and away to transmit outside the body. The clock and transmit functionalitymay, in certain embodiments, be omitted. The transmitter could be an RFlink or conductive link to move information from local data storage toan external data storage.

For the external signal receivers, embodiments include structures thathave electrodes opposed to the skin, the demodulator, storage, andpower. The communication may be wireless or performed over one or moreconductive media, e.g., wires, optical fibers, etc.

In certain embodiments, the same electrodes are used for receiving andtransmitting signals. One mode might be to have for example a wristwatchwhich is conductively in contact with the body, where to move the datafrom the implant to the wristwatch one would send currents out the padsand those would be received by the wristwatch. There are a number of RFtechniques for getting the transmission out of the body that may beemployed, such as inductive protocols that employ coils. Alternatively,one could employ electric fields, where one would use insulatedelectrodes, not conductively contacted electrodes.

In certain embodiments, the components or functional blocks of thepresent receivers are present on integrated circuits, where theintegrated circuits include a number of distinct functional blocks,i.e., modules. Within a given receiver, at least some of, e.g., two ormore, up to an including all of, the functional blocks may be present ina single integrated circuit in the receiver. By single integratedcircuit is meant a single circuit structure that includes all of thedifferent functional blocks. As such, the integrated circuit is amonolithic integrated circuit (also known as IC, microcircuit,microchip, silicon chip, computer chip or chip) that is a miniaturizedelectronic circuit (which may include semiconductor devices, as well aspassive components) that has been manufactured in the surface of a thinsubstrate of semiconductor material. The integrated circuits of certainembodiments of the present invention may be hybrid integrated circuits,which are miniaturized electronic circuits constructed of individualsemiconductor devices, as well as passive components, bonded to asubstrate or circuit board.

As reviewed above, the signal receivers exhibit reliable decoding of anencoded signal even in the presence of substantial noise and a low SNR.This functional aspect of the receivers of the invention is provided byone or more of: Coherent demodulation, e.g., Costas loop demodulation,accurate low overhead iterative decoding, Forward Error correction andNoise Cancellation.

Demodulator

In one embodiment, the binary code is modulated to the carrier signalusing binary phase shift keying (BPSK). In standard BPSK the carriersignal is modulated by shifting its phase by 0° for a binary “0” and180° for a binary “1.” Note that this is an arbitrary assignment, and aphase shift of 0° may instead correspond to a binary “1”, with a phaseshift of 180° corresponding to a binary “0.” This allows a lower signalto noise ratio (SNR) than frequency shift keying or amplitude shiftkeying, allowing the binary code to be accurately decoded in thepresence of a greater amount of noise. This is useful in manyenvironments where there are many sources of noise in the same frequencyspectrum, such as in a hospital.

The in-vivo transmission decoder can successfully decode an incomingBPSK signal with negligible error with an SNR as low as about 3 dB, morespecifically about 6 dB, most specifically about 7.7 dB. The signal canbe decoded with about 10% error in the decoded bits with an SNR as lowas about 0 dB, more specifically about 3 dB, most specifically about 4.7dB. The actual minimal SNR needed depends on the amount of error that isallowable. With higher allowable error, the signal can be successfullydecoded with a lower SNR. With error checking algorithms, some error maybe acceptable, and the SNR could be even lower, while still successfullydecoding the signal.

Because the original data bit signal may be a square wave which containssome high frequency components, the modulated signal may have some highfrequency components as well. These can corrupt the signal depending onthe sampling rate. To alleviate this, an anti-aliasing filter can beincluded in some embodiments. The anti-aliasing filter can filter outthe high frequency components and clean up the analog signal beforesampling. Typically, a low-pass filter with a cutoff of one half of thesampling frequency is used.

In one embodiment of the inventive in-vivo transmission decoder, thereceiver can have an analog to digital converter to sample the inputsignal. The sampling rate can be varied according to the frequency ofthe incoming signal, noise level, or other factors.

In one embodiment of the in-vivo transmission decoder, the sampling ratecan be actively adjusted according to measured factors such as SNR. Whenmore noise is present, a higher sampling rate can be used, so that thesignal can still be decoded accurately. However, when the SNR is higher,the sampling rate can be lowered without affecting the accuracy of therecovered signal. The in-vivo transmission decoder can compare themeasured SNR to a threshold, and use the ratio to adjust the samplingrate. There can be a lower limit past which the sampling rate won't belowered.

In laboratory tests conducted by some of the present inventors, thesignal was successfully decoded in the presence of noise with a samplingrate as low as four times the frequency of the incoming signal. Thein-vivo transmission decoder can accurately decode the received signalwith a sampling rate as low as about 2 times the frequency of thereceived signal, more specifically about 3 times the frequency of theincoming signal, most specifically about 4 times the frequency of theincoming signal. By actively adjusting the sampling rate to be as low asnecessary, the power used by the receiver can be conserved.

In one embodiment of the in-vivo transmission decoder, there is anautomatic gain control (AGC) block, which actively adjusts the gain tomaximize the effectiveness of the Costas loop. The AGC block can alsofind the strongest frequency of the received signal, and tune othercomponents to adjust for that. This allows the receiver to activelyadjust to variations in frequency and power of the incoming signal, aswell as drift of the signal over time.

In one embodiment, the AGC block includes a Fast Fourier Transform (FFT)calculation, which is used to find the power spectrum and strongfrequency of the incoming signal. Because the AGC block needs a group ofpoints to calculate the FFT, a buffer can be used. The buffer can be setto collect a certain number of points before sending them on to the FFTfor processing. The size of the buffer used can vary depending oncharacteristics of the incoming signal, such as signal uniformity andcycle length. The buffer size should be small enough to provide fastprocessing and adjustment to changes in the signal, but large enoughthat the FFT results do not vary widely with instantaneous changes inthe signal.

Once the signal is buffered, the signal can be passed to the FFTfunction. This portion computes the FFT of the input signal, giving thepower spectrum. The block then locates the frequency that has thehighest amplitude in the FFT signal, f_(max). The FFT calculationrequires a finite number of samples from the incoming signal in order toproduce accurate results, which is why the buffer is used. The frequencyinformation is passed on to subsequent blocks and can be used to tunevarious components, such as the band-pass filters and voltage controlledoscillators of a Costas loop.

The AGC block also amplifies the signal, adjusting the gain to achieve apredetermined signal power. The strength of the received signal willvary depending on many factors, such as location and orientation of thetransmitter. To adjust for this, the AGC block finds the amplitude ofthe strongest frequency component in the power spectrum. This amplitudevalue is divided into a normalized power value which gives the propergain to apply to achieve that signal strength. The original digitalsignal which was input into the ACG block is then amplified by thecalculated gain and passed on.

The amplified digital signal can then be passed through a band-passfilter before entering the Costas loop. The band-pass filter can betuned to have a center frequency equal to f_(max), the strongestfrequency component found in the AGC block. This is included to clean upthe signal further and eliminate noise components at frequencies thatare not part of the transmitted signal. Although the transmitter isdesigned to output the data signal at a set carrier frequency, theactual output of each unit may vary. By actively tuning the centerfrequency to f_(max), the band-pass filter can adapt to variations inthe frequency sent out by the transmitter, and to frequency drift of thesignal over time. The bandwidth of the band-pass filter can be set to apercentage of the strongest frequency of the incoming signal.Alternatively, the bandwidth can be set to a specific value.

In some embodiments, there can be a first-in first-out block includedbefore the FFT in the AGC block. This can be implemented in cases wherethe processing time of subsequent blocks is longer than the rate of thedata coming in. The signal is then sent into a Costas loop fordemodulation of the signal. The Costas loop reconstructs a replica ofthe carrier which is locked in frequency and phase to the incomingcarrier, so the phase of the received signal can be extracted, giving anapproximation of the original binary signal.

The Costas loop employed can be very similar to those known in the art,with the exception that the voltage-controlled oscillator is tuned tof_(max). This allows the Costas loop to adapt to changes in thetransmitted carrier frequency and lock on to the correct signal. In labtests conducted by some of the present inventors, the receiver was ableto adjust to an instantaneous change of up to about +/−10 kHz, whenoriginally configured to receive a 100 kHz signal.

The in-vivo transmission decoder can track an instantaneous change infrequency of up to about 25% of the signal frequency, more specificallyup to about 25% of the signal frequency, most specifically up to about10% of the incoming signal. Depending on the size of the frequencychange, the receiver can typically lock onto the new frequency within afew cycles of the waveform.

In another embodiment, there can be an integrator added to the CostasLoop between the multiplier and the low-pass filter in the VCO branch.This helps to smooth out the signal more than the low-pass filter alone.In another embodiment, there can be a low-pass filter added to theoutput of the Costas loop to clean up the signal before the signalrecovery block.

The Costas loop can also output the detected power of the signal. Insome embodiments, this can be used to tune the gain in the AGC block.This can be used in addition to or instead of the other gainadjustments.

After the signal goes through the Costas loop, the signal clock must beextracted in order to determine when each bit begins and ends. One wayof accomplishing this is through the use of an Early-Late Gate. TheEarly-Late Gate is a phase locked loop with two integrators which eachmaintain a running sum of half of the symbol period, T, of the incomingdata. The early gate sums the data during the first half of the symbolperiod, or from time t−T/2 to t. The late gate sums the signal duringthe second half of the symbol period, or from time t to t+T/2. The lategate is then subtracted from the early gate, and this difference isoutputted. This output will be zero as long as a string of 0's or 1's isreceived. When there is a transition from a 1 to a 0, or from a 0 to a1, the early late-gate output becomes non-zero. The next time, t, thatthe output becomes zero will be the center of the corresponding symbol.

In order to compensate for different sampling rates and signalfrequencies, the number of samples to use for the early and late gatesis actively computed instead of using a standard value. With a signalwhich is set to broadcast each bit for 16 cycles of a sine wave, thenumber of sampled points in half of the symbol period will be the timeneeded for 8 periods of the sine wave divided by the time betweensamples. Or, put in different terms:

T _(g)=8f _(s) /f _(c)

Where T_(g) is the time of the early gate and late gate, f_(s) is thesampling frequency and f_(c) is the frequency of the transmitted signal.Frequency fc can be found by using the frequency that the VCO locks ontoin the Costas loop.

When a known preamble or start sequence is sent, the time that aspecific bit occurs can be determined. As an example, assume a preambleof a sequence of 16 zeros is followed by a known start sequence of 0010,which is then followed by an 8 bit ID sequence and a 4 bit sleep periodwhere no signal is sent. The algorithm can first identify where thesequence of zeros occurs by looking for a period of no change in thesignal. This prevents the timing problems that would occur if thereceiver begins picking up the signal in the middle of a data packet.Since the period of zeros is longer than any other possible sequence ofno changes, the algorithm can correctly identify where this preambleoccurs. Once the preamble is identified, the algorithm can begin lookingfor the start sequence. During the first two zeros of the example startsequence, the early-late gate output will remain zero. The firstnon-zero value will occur at the transition from 0 to 1. The early-lategate will then cross zero again at time=t₃, the center of the 1 bit inthe signal. Since the symbol period, T, is known, once the time at whichthe third bit of the start bit sequence occurs is known, the time forall other symbols can be determined. In this example, the n^(th) symbolwill occur at t_(n)=t₃+(n−3)T.

In practice, the early-late gate output may not be exactly zero duringnon-transition periods, but will instead hover around zero due to noise.In order to mark the non-zero point, a threshold is set which is abovethe level of noise, but below the amplitude of a bit. The receiver cancompare the early-late gate output against this threshold, and set aflag when it is crossed. Once the threshold is crossed, the receiverthen looks for a zero-crossing in the signal.

There is a 180° phase ambiguity which is inherent in any Costas loopimplementation, meaning the Costas loop is just as likely to lock in tothe phase of a “0” as it is a “1”. There are several ways to deal withthis which are well known in the art. In one embodiment, once the symboltiming is recovered, the known start sequence can be looked at in theCostas loop output. Two threshold values can be used, one positive andone negative. When the positive threshold is passed, the index of thedigital signal can be stored, and compared against the index stored forthe negative threshold to determine which threshold was passed first. Inthe case of the known start bit 0010, if the positive threshold ispassed first, that would indicate that a larger Costas loop outputrepresents a “0,” while a smaller output represents a “1.” If thenegative threshold is passed first, that would indicate that a largerCostas output represents a “1,” while a smaller output represents a “0.”At this stage, the bit sequence can be accurately extracted, and the IDof the transmitter can be identified.

Other techniques for symbol timing recovery that can be utilized includedifferential decoding, Gardner timing recovery, squaring timingrecovery, and Mueller-Mueller timing recovery.

The data from the transmitter can be repeated at regular intervals. Thisreduces error and allows the receiver many opportunities to decode thesignal. Once the symbol recovery algorithm identifies the start bitsequence and begins reading the bits, a delay can be used to restart thesymbol recovery algorithm for the next data packet. Because of theCostas loop ambiguity, the symbol timing recovery algorithm will need tobe restarted for each data packet. Because the ID will be a known numberof bits, a predetermined delay can be applied.

FIG. 1 shows a high-level flow chart of one embodiment of the receiveralgorithm. The input signal 1 is picked up by an antenna and fed intoAGC block 3. The AGC block 3 samples the signal, finds the strongfrequency, and amplifies the signal to a normalized power. The Costasloop block 5 then demodulates the incoming digital signal. Symbolrecovery block 7 is used for symbol timing recovery of the Costas loopoutput. After the symbol recovery block 7, the signal has beendemodulated and the timing has been recovered, and the bit sequence 9 isextracted.

For the purposes of demonstrating the inventive algorithm, a sample datasignal will be used. The data signal used for this example is a 32 bitsignal. The first 16 bits are known to be all zero. The zero period isfollowed by a start preamble which is 0010. After the preamble is the8-bit ID sequence. The remaining 4 bits are a quiet period. In thisexample, the binary signal is modulated using BPSK to a carrier signalwhich transmits at a nominal frequency of 100 kHz. Each bit is 16periods of the sine wave long, meaning for each bit the sine wave willbe in the corresponding phase for 16 periods. This corresponds to anoverall time for each 32 bit signal of about 5.12 ms. It is understoodthat this sample data signal is only an example, and the receiveralgorithm can be applied to any BPSK signal. Also, one of the keyaspects of the inventive algorithm is that it can account for variationsin the actual carrier frequency of the transmitted signal, so thetransmitted signal need not be extremely precise between differenttransmitters.

The algorithms discussed below were created using Simulink as a tool.The algorithms can then be transferred to hardware using knowntechniques. One such technique is to use Mathworks Real-Time Workshop toconvert the Simulink developed algorithm into C code. Then TexasInstruments Code Composer Studio, or other similar development tool, canbe used to convert the C code into assembly language. The assemblylanguage can be programmed onto a digital signal processing (DSP) chip,such as Texas Instruments model TMS320VC5509 or a similar chip.

FIG. 2 shows a block diagram created in Simulink that shows oneembodiment of the AGC block and Costas loop from FIG. 1. Incoming data15 is actual data received in an animal study, sampled at 2 MHz. Theanimal study used a PCB inserted in the stomach of a pig to transmit thedata signal. The signal was received by subcutaneous titanium electrodesand skin patches. This data was sampled at 2 MHz and fed into thesoftware at data block 15. Since this is actual data which was collectedin-vivo, it is a demonstration of the effectiveness of the algorithm inan in-vivo setting. The data 15 fed into buffer 17, which is set tocollect 2¹⁵ points. With a sampling rate of 2 MHz and a data period ofabout 5.12 ms, this means the buffer collects a little over 3 packets ofdata. This can be adjusted depending on various factors such as signalcharacteristics and noise level. Using more packets of data gives a morestable FFT that will not change as much in successive iterations. Sincethe output of the FFT block will be used to tune the gain and centerfrequency of other components, these variables will not have to beadjusted as much and will not vary as widely as if a smaller set of datais used for the FFT.

The buffered output is then sent to a first-in first-out (FIFO) block 19which manages the data to ensure that it is processed in order and willstore it until the subsequent blocks are ready for it. This may benecessary because the FFT block, Costas loop, and Early-Late Gate cantake time to complete.

The data is then sent to a FFT block 21, which calculates the fastFourier transform of the amount of incoming data determined by thebuffer 17. The FFT block finds the strongest frequency by finding thefrequency which gives the maximum value in the FFT. This frequency isoutput as a variable 25, labeled “signal_freq”, which can be used byother blocks.

The Costas loop works best when the power of the incoming signal isnormalized. This is done in the FFT block also. The amplitude of thepower spectrum given by the FFT at the frequency “signal_freq” is foundand compared to a constant value which represents the desired power forthe Costas loop. This gives the gain 25 which is necessary to achievethat signal power, and this gain is applied. The FFT block 21 thenoutputs signal 27 which is the incoming signal 29 amplified by thecalculated gain 25.

This amplified signal is fed into the Costas loop 31. The Costas loopdemodulates the BPSK signal. The Costas loop used is similar to thosewhich are well known in the art, except that the components can beactively tuned according to measured characteristics of the incomingsignal. The Costas loop will be discussed in greater detail below. TheCostas loop output 33 is sent to a matlab workspace where the finalsymbol decoding is done, including an Early-Late Gate.

FIG. 3 shows a more detailed block diagram of FFT block 21 from FIG. 2.The output from the FIFO enters FFT block 21 at input 35. Magnitude FFTblock 37 performs a fast Fourier Transform, which gives the powerspectrum of the signal as a function of frequency. Maximum block 39finds the point in FFT 41 where the amplitude is at a maximum, andoutputs the value 43 and index 45 of where that point occurs in the datastring. The maximum value 43 is fed into divider block 47. Divider block47 takes the normalized power constant 49, which is a predeterminedvalue of the desired signal power, and divides it by maximum power value43, which yields signal gain 51. Signal gain 51 is then applied to input35 in multiplier block 53 in order to achieve a signal with a normalizedpower for the Costas loop. Before being sent to the Costas loop, theamplified signal 55 is unbuffered by unbuffer block 57 in order toconvert the signal back to a steady stream. Switch 59 is there to dealwith a problem with dividing by zero in the software, but is notnecessary for the algorithm. The output of the FFT block is theamplified, unbuffered signal 61.

The FFT block in FIG. 3 also finds and outputs the frequency at whichthe maximum amplitude of the power spectrum of the signal occurs.Maximum block 39 outputs index 45 which is the index of the data pointin the digital FFT string. The index 45 of the maximum point is dividedby the buffer size 63 in divider block 65. This gives the relativeposition of the maximum point in the range of 0 to the maximum frequencyof the spectrum. Constant 67 is one divided by the sampling time, whichwill give the maximum frequency of the spectrum. The fractional value 69found in divider block 65 is then multiplied by frequency spectrumconstant 67 to yield the absolute frequency value 71 of the maximumpower in the signal. This is set as a constant 73 which can be used inother blocks to tune components such as filters and voltage controlledoscillators.

FIG. 4 shows a more detailed block diagram of Costas loop 31 from FIG.2. The amplified, unbuffered output from the FFT block enters the Costasloop at input 75. It is band-pass filtered by transfer functions 77 and79. The use of two filters gives a sharper roll-off than if one filterwere used. The transfer functions of filters 77 and 79 are defined usingvariables in Simulink. The center frequency of band-pass filters 77 and79 is set to be the “signal_freq” variable 73 from the FFT block in FIG.3. The bandwidth of the band-pass filters 77 and 79 are set to be oneeighth the center frequency.

By actively adjusting the center frequency of the filters at the inputof the Costas loop, the receiver can adjust to changes in the transmitfrequency while maintaining a relatively narrow band. This allows thetransmitter-receiver system to be used under varying conditions, such assupply voltage and temperature, which may alter the transmittedfrequency. This is especially useful when the signal is to betransmitted and received in a poor signaling environment such as thebody, and areas where a lot of signal noise is present, such as inhospitals.

The rest of the Costas loop is standard and well-known in the art, withthe exception of added low pass filter 81, integrator 83, and poweroutput 85. The added low-pass filter 81 and integrator 83 are includedto further clean up the signal, but are not necessary for the Costasloop to work. Power output 85 is included in Simulink in order tomeasure the signal-to-noise ratio (SNR), but does not play a part in thesignal analysis in the current embodiment. In other embodiments, thepower output 85 can be used to tune other components. For example, thepower output 85 can be linked back to the gain stage 53 of the FFT blockin FIG. 3. The output of the Costas loop is essentially a filteredversion of the original binary code, except that the polarity can bereversed depending on whether the Costas loop locked onto a “0” or a“1.”

FIG. 5 shows an embodiment of the symbol recovery block 13 from FIG. 1.In this embodiment, the symbol recovery block takes the output of theCostas loop and performs an early-late gate calculation 87. Theearly-late gate results are used to identify the beginning of the IDsequence in block 89. This block extracts the timing of the signal toidentify the indices at which the center of each bit occurs, and alsoidentifies the start bit in order to locate where the ID code starts.From this information, the index of the Costas loop output whichrepresents the phase of each bit can be found. Block 91 determines thepolarity of the lock phase in the Costas loop. This finds whether theCostas loop locked into the phase of a binary “1” or “0,” and setsdecision points for each bit. Next, block 93 looks at the Costas loopoutput signal at each ID index that was found in block 89 and decideswhether each is a “1” or a “0.” At that point, the 8-bit ID has beensuccessfully extracted.

In certain embodiments, the architecture is configured in view of theneed to demodulate/decode where the uncertainty in the carrier frequencyis +/−20%, where a Costas loop (e.g., as described above) might be ableto lock onto a signal where the carrier uncertainty is +/−6%, and wherecoherent detection requires a carrier uncertainty of <1%. In certainembodiments, overall packaged circuit size is important to achieve adevice that is comfortably usable. In addition, power consumption isalso important for battery longevity in certain embodiments.

FIG. 6A illustrates an architecture employed in certain embodiments. Asshown in FIG. 6A, the structure gains up the signal (A), applies ananti-aliasing filter (B), digitizes the signal using an ADC (C), andthen identifies the carrier, demodulates and decodes using DSPtechniques coded into a general purpose DSP or microcontroller (D). Theanti-aliasing filter is designed in consideration of the range ofcarrier frequencies and the sampling rate of the ADC. The sampling rateof the ADC is in certain embodiments at least >3× the highest possiblecarrier frequency, such as 4× the highest possible carrier frequency.The resolution is selected based upon the dynamic range of the signal.

In the alternative configuration illustrated in FIG. 6B, the carrieridentification, demodulation, and decode functions are performed by acombination of ASIC/FPGA/Co-Processor (D) and low powermicrocontroller/processor (E). The ASIC/FPGA/Co-Processor implement themath intensive functions that are part of the carrier identification,demodulation, and decoding. These functions may include FFT, filters,decimation, multiplication, etc.

FIG. 6C illustrates an architecture according to an embodiment thatimplements much of the signal processing using analog circuittechniques. Block (A) still gains up the received signal. Block (B)implements a band-pass filter. In Embodiments of these circuits, thebandwidth is set at f/8 where f is the anticipated carrier frequency.Block (C) implements a demodulation function. Block (D) is an ADC. Thesampling rate determined by the maximum symbol rate*4. Decoding isperformed in a DSP or microprocessor (E), but its performancerequirements are much relaxed compared to that in FIG. 6A. Blocks (B),(C), and (D) are duplicated with separate distinct bandwidths to therange of carriers. Alternatively, the decode function may be implementedusing analog circuitry, further reducing the specifications on block(E).

Each figure contemplates using discrete components to implement thecircuitry. However 2 or more blocks in any figure may be implemented inan ASIC, thereby reducing the component count and therefore the overallsize. While FIG. 6C may have a larger component count (and size) ifimplemented discretely, it could also be implemented as an ASIC. Any oneof the circuits illustrated in FIGS. 6A to 6C could be implemented in asingle chip (system on chip—SOC). In certain embodiments, the onlylimitation may be that the input referred noise on block (A) limits theoverall performance of the system. Minimum noise requires a bi-polartransistor input stage which is not possible on standard digital ICprocesses, but found in many “mixed-signal” processes.

Coherent Demodulation

The demodulation of BPSK in the presence of AWGN (Additive WhiteGaussian Noise) is performed in certain embodiments to minimize BER (BitError Rate) using coherent demodulation.

In these embodiments, the in vivo transmitter facilitates the receivercoherent demodulation process by sending a pilot carrier in the “frontporch” of each burst of BPSK modulation. This protocol provides a stablecarrier at full amplitude and a reference phase that corresponds withthe transmission of a 0 bit. The presence of a front porch gives auseful detection signature to the receiver and a large number of carriercycles for accurate estimation of the carrier frequency and phase.

An additional practical use is made of the carrier frequency to simplifyderivation of the data rate. The transmitted signal is formatted to havethe data clock frequency an integer division of the carrier frequency.This permits easy and rapid data clock acquisition once the carrieracquisition has been accomplished.

The receiver samples the incoming signal at a rate of around 4 times thecarrier frequency in certain embodiments. This signal is mixed with aDDS (Direct Digital Synthesizer) set to the nominal carrier frequency tocreate complex baseband (real and imaginary components). The output ofthe mixer is low pass filtered and decimated. The low pass filterbandwidth must be sufficiently wide to capture frequencies in the banddue to carrier oscillator uncertainty and frequency hopping dither. Thefrequency of the BPSK is subsequently in the vicinity of 0 Hz with afrequency accuracy of +/−20%.

The receiver squares the complex baseband BPSK signal to create a strongdouble frequency line. The front porch signal and following BPSKmodulation all contribute to this line. The squared complex time domainsignal is transformed to the frequency domain using an FFT (Fast FourierTransform). The peak energy bin is identified as the 2× carrierfrequency. This frequency is divided by two to provide an estimate ofthe carrier offset frequency to about 0.1% accuracy using a 1024 pointFFT.

The complex baseband signal is then mixed a second time with thedetermined offset frequency. The result after narrow band low passfiltering is a complex BPSK signal centered at 0 Hz with an accuracy of0.1%. The bandwidth of the narrow band low pass filter corresponds withthe half bandwidth of the BPSK signal.

The front porch signal is then extracted. The frequency offset isdetermined by first computing the phase (phi=arctan(imag/real)) of allsample points in the front porch, and then estimating the slope of phivs. time using a least mean square fit to a line. The slope of the linecorresponds to the residual frequency offset. The complex basebandsignal is then mixed a third time to remove this frequency offset withan accuracy better than 0.01%.

The complex signal front porch is then averaged to determine the meanimaginary and real values. The arctan(mean imag/mean real) provides thefront porch phase. A rotator factor is computed based on this phase torotate the BPSK on to the imaginary axis with the front porch at 270degrees.

A second averaging is then performed on the entire rotated BPSK signalto identify the center of gravity of the 90 degree (data=1) and the BPSKis rotated in a similar manner to center this on the imaginary axis. Theimaginary signal is then sliced to extract the data.

The sliced data is strobed with a data clock that is derived from theprior determination of the carrier frequency and apriori knowledge ofthe integer factor relating the carrier frequency to the data clockfrequency.

In embodiments of the above protocols, it is assumed that the carrierfrequency holds to a sufficient accuracy in frequency and phase throughthe duration of the entire burst. In the event that this is not thecase, adaptive frequency tracking can be implemented using a decisiondirected carrier recovery phase locked loop such, as the Costas loop asdescribed above. The Costas loop operates by driving a rotator tomaintain zero average error in phase of the baseband signal.

Accurate, Low Overhead Iterative Decoding

In certain embodiments, the receivers include an accurate, low overheadinterative decoder, also referred to herein as a communications decoder.The communications decoder provides, for the first time, highly accuratecommunications in a simple, elegant, and cost-effective manner despitethe presence of significant signal distortion due to noise and otherfactors. The communications decoder utilizes error correcting codes anda simple, iterative process to achieve the decoding results. Thecommunications decoder can be used across multiple and variedapplications to realize a low cost, high coding gain.

Broadly, an embodiment of a communications decoder provides decodingcapabilities for data communications. An embodiment of a communicationsdecoder provides a high coding gain with minimal overhead. In someinstances, the communications decoder facilitates data transmissionrates close to the theoretical maximum, the Shannon Limit, whileminimizing processing overhead. The low overhead ensures cost-effectiveimplementations. Various implementations of the present inventioninclude hardware, software, and circuitry.

Further, the communications decoder is applicable to any communicationsenvironment, particularly noisy communications environments, and notjust to receivers of signals transmitted from in vivo transmitters. Forexample, the communications environments include inter-body andintra-body communications; deep space transmissions; opticalcommunications; radio communications; storage media; multimedia devices;and wireless communications. Multimedia devices include, for example,audio and multimedia receivers associated telephones, stereos, audioplayers, and multimedia players. Deep space transmissions includesatellite communication devices. Wireless communications includewireless devices such as wireless headsets; audio and multimedia devicesand equipment, such as audio players and multimedia players; telephones,including mobile and cordless telephones; and computers andcomputer-related devices and components, such as printers.

However, for ease of description, the communications decoder will bedescribed further primarily in terms of embodiments in which it ispresent in a receiver of an in vivo transmitted signal.

Inter-body and intra-body communications include, for example, software,circuitry, and devices associated with data reception from implantable,ingestible, insertable, and attachable medical devices associated withthe human body or other living organisms. The medical devices comprise,integrate, or are otherwise associated with the communications decoder.One example is a receiver such as is described in PCT/US2006/16370titled “Pharma-Informatics System” and filed on Apr. 28, 2006; as wellas U.S. Provisional Application Ser. No. 60/887,780 titled “SignalReceivers for Pharma-Informatics Systems” filed on Feb. 1, 2007 and U.S.Provisional Application Ser. No. 60/956,694 titled “Personal HealthSignal Receivers” filed on Aug. 18, 2007. Each of the foregoingapplications is hereby incorporated by reference in its entirety.

More particularly, communication between devices can be accomplishedusing various techniques. At origin, for example, an encoder deviceconverts (modulates) data formatted as binary digits (bits) totransmission symbols associated with analog signals. A transmittertransmits the data to a receiver. At destination, a receiver measureseach analog signal of the analog signals. Based on the measurement, adecoder converts (demodulates) each analog signal to a bit and assemblesthe converted bits into data. Some or all of the data, however, may bein error. One common error occurs in noisy communications environmentswhen the noise changes the signal to a measurement that, whendemodulated, results in a bit that does not coincide with the originalbit transmitted at origin.

Using certain current error detection techniques, the presence of errorsin data can be detected. Current error detection techniques include theuse of error correcting codes such as turbo codes and low-densityparity-check (LDPC) codes.

Under existing turbo codes methods, the transmitter or encoder generatesthree variations, or sub-blocks, of the data: the original data, anencoded version of the original data, and an encoded version of thepermutated data. Each of the sub-blocks is transmitted. The receiverconverts the signals of the three sub-blocks into “most likely” data andcompares the three sets of estimated data. A decision is taken from thecomparison to arrive at a final “most likely” decision for the decodeddata. Such a method is complex and costly.

Under existing LDPC code methods, the transmitter or other deviceencodes the original data (bits) with one or more error correcting codes(hereinafter, “codes”), as discussed in an article entitled “Low PowerDigital Communication in Implantable Devices Using Volume Conduction ofBiological Tissues”, which is incorporated here in its entirety.(Heung-No Lee, R. J. Sclabassi, Mingui Sun, and Ning Yao, “Low PowerDigital Communication in Implantable Devices Using Volume Conduction ofBiological Tissues”, Proceedings of the 28^(th) IEEE EMBD AnnualInternational Conference New York City, USA, Aug. 30-Sep. 3, 2006, pp.6249-6252.) The codes include parity codes, Hamming codes, and Golaycodes. The transmitter converts the bit set to analog signals, e.g.,transmission symbols, and transmits the transmission symbols. Thereceiver decodes the analog signals to the “most likely” bit. Putanother way, the receiver rounds the measurement of the transmittedsignal to the nearest bit.

The rounding of the measurement to the nearest bit, however, does notalways result in correct data. In particular, noise can corrupt thesignal. This can result in a signal measurement that, when rounded tothe nearest bit, does not correspond to the original bit converted andtransmitted at origin.

To ascertain if such errors have occurred, an error check of the bitscan be performed using the codes. Existing parity code methods employthe use of a parity code to check for parity errors at destination. Thepresence of a parity error suggests one or more occurrences of error ina bit set, i.e., one or more converted bits at destination do not matchthe corresponding bit generated at origin. The actual bit or bits inerror are not necessarily identified. Therefore, although the bit set isknown to contain one or more errors, the bit set itself, and thus theentire data, are not accurate at destination. The data might have to beretransmitted. Retransmission of the data results in costly, cumbersomeoperations. Further, even numbers of errors in a set of bits are notnecessarily identifiable using current parity code methods. Therefore,the destination data can be undetectably corrupted. In addition, currentLDPC decoding techniques are complex and costly.

Various embodiments of the inventive communications decoder of thepresent invention use error correcting codes and a simple, uniqueprocess to “urge” a measurement signal associated with a bit in errortoward a measurement signal associated with the correct, original bit,thus improving the likelihood of identifying destination data thatmatches the data encoded at origin and significantly improving dataaccuracy at destination. The simple, unique process facilitatesefficient implementations. The low overhead associated with the simple,unique process minimizes costs. LDPC decoding is far less complex byusing the iterative communications decoder of the present invention.

FIG. 7 is a system view of a communication environment 100 including adecoder module 112, according to one embodiment. The communicationenvironment 100 is associated with, for example, unencoded data 102, anencoder module 104, a transmitter module 106, encoded data 108, areceiver module 110, the decoder module 112, and decoded data 114.

Particularly, in the communication environment 100 of FIG. 7, unencodeddata 102, or a portion of the unencoded data 102, is encoded by theencoder module 104. The transmitter module 106 transmits the encodeddata 108 via data channel 116. The receiver module 110 receives theencoded data 108. The decoder module 112 decodes the encoded data 108and generates decoded data 114. In various embodiments, various modulesare implemented individually or integrated into a particular device orsoftware. For example, the receiver module 110 and the decoder module112 are integrated into a device such as a receiver and/or a softwaremodule. Further, various modules are fully or partially integrated withor implemented as hardware devices. For example, the transmitter module106 is implemented as, or integrated with, a transmitter. In anotherexample, the decoder module 112 is integrated as software, circuitry, orcombinations thereof.

Generally, the decoder module 112 generates the decoded data 114 viavariations of the following technique. For each bit set of the encodeddata, a set of measured signals associated with the encoded data isrounded to the nearest most likely possible measurement if no noise werepresent, e.g., to a nearest transmission symbol, as further describedwith respect to FIG. 9B. The set of transmission symbols is convertedinto a set of hard code decision values. An error check is performed onthe set of hard code decision values, as further described with respectto FIG. 9C. The set of measured signals is adjusted based on an outcomeof the error check of the set of hard code decision values, as furtherdescribed with respect to FIG. 9D. The foregoing is performed in passesacross all measured signal sets of the encoded data until apredetermined stopping condition is met. A more detailed discussionfollows.

More particularly, FIG. 8A is an illustration of the unencoded data 102,according to one embodiment. The unencoded data 102 include all or aportion of datapoints associated with the unencoded data, represented inFIG. 8A as bits 202. Various embodiments include other representations.

Particularly, in FIG. 8A, the unencoded data 102 are grouped intosubsets of datapoints, e.g., subsets of bits 202. Such subsets ofdatapoints are sometimes referred to as “bit sets” 204. Bit sets 204 areunstructured or structured in various arrangements. Such arrangementsinclude matrices, multidimensional hypercubes, and other geometries. Toillustrate, the unencoded data 102 are shown as 16 bit sets 204 arrangedin a two dimensional matrix having rows one through four (R1-R4,respectively) and columns one through four (C1-C4, respectively).

FIG. 8B is an illustration of the encoded data 108. In general, theunencoded data 102 are encoded with one or more error correcting codes206 to generate the encoded data 108. In one embodiment, an errorcorrecting code 206 is generated for each bit set 204 of the unencodeddata 102. The error correcting codes 206 include parity codes, Hammingcodes, Golay codes, and other error correcting codes.

Particularly, in FIG. 8B, an error correcting code 206 such as a paritycode is associated with, e.g., included in, each bit set 204 of theunencoded data 102, i.e., rows R1 through R4 and columns C1 through C4.For example, in row R1, column C5 an error correcting code 206 of “0” isassociated with the bit set 204 of row R1 (even parity). In row R2,column C5 an error correcting code 206 of “0” is associated with the bitset 204 of row R2 (even parity). In row R5, column C1 an errorcorrecting code 206 of “0” is associated with the bit set 204 of column1 (even parity). In row R5, column C5 a code of “0” is associated withthe bit sets 204 of row R5 and column C5 (parity on parity, evenparity).

FIG. 8C is an illustration of transmission symbols 208, according to oneembodiment. Particularly, in FIG. 8C, the encoded data 108, e.g., theunencoded data 102 and the error correcting codes 206, are convertedinto the transmission symbols 208. One example of transmission symbolsare signals modulated for transmission. The transmission symbols 208 aregrouped into subsets of the transmission symbols 208, sometimes referredto as the transmission symbol sets 210. The transmission symbol sets 210correspond to the bit sets 204 (FIG. 8B). For example, the transmissionsymbol set 210 at row one R1 corresponds to the bit set 204 at row oneR1 (FIG. 8B).

Various methods convert and transmit the encoded data 108. For example,binary phase-shift keying (BPSK) is used to transmit the encoded data108 over a radio channel. Each of the bits 202 is converted to a carrierphase of 0 degrees if the bit 202 is 0 or to a carrier phase of 180degrees if the bit 202 is 1. This conversion corresponds to I=1 for bitsof 0 and I=−1 for bits of 1, where the output signal is in the form of:

Vout=Itx*cos(w*t),

where Itx is the baseband amplitude signal, w is the radial carrierfrequency, t is time and Vout is the transmitted voltage. Other methodsof conversion and transmission can be used including, for example,quaternary or quadriphase PSK (QPSK) or quadrature amplitude modulation(QAM).

The transmitted signals are received by the receiver module 110. Thereceiver module 110 measures the received signals. The measured signalsare arranged according to the original, corresponding bits sets 204 ofthe encoded data 108.

FIG. 9A is an illustration of measured signals 302, according to oneembodiment. Particularly, in FIG. 9A, each received signal correspondingto each transmission symbol 208 (FIG. 8B) can be measured. The measuredsignals 302 are grouped into subsets of the measured signals 302,sometimes referred to as measured signal sets 304. The measured signalsets 304 correspond to the transmission symbol sets 210 (FIG. 8C) and tothe bits sets 204 (FIG. 8B). For example, the measured signal set at rowone R1 corresponds to the transmission symbol set 210 at row one R1(FIG. 8C) and to the bit set 204 at row one R1 (FIG. 8B).

FIG. 9B is an illustration of transmission symbols 208, according to oneembodiment. Particularly, in FIG. 9B, the measured signals 302 (FIG. 9A)is rounded to the nearest possible measurement if no noise were present,e.g., to the nearest transmission symbol 208 of (1, −1). Thus, forexample, “0.3” is rounded up to 1, −0.9 is rounded down to −1, and soforth. The transmission symbols 208 reflect the rounded values of themeasured signals of 302 (FIG. 8B).

FIG. 9C is an illustration of hard code decision values 306, accordingto one embodiment. Particularly, in FIG. 9C, the transmission symbols208 (FIG. 9B) are converted into hard code decision values 306. The hardcode decision values 306 are grouped into subsets, sometimes referred toas hard code decision value sets 308. The hard code decision value sets308 correspond to the transmission symbol sets 208 (FIG. 9B), to themeasured signal sets 304 (FIG. 9A), to the transmission symbol sets 210(FIG. 8C), and to the bits sets 204 (FIG. 8B).

More particularly, the transmission symbols 208 are converted to binaryform (demodulated) to generate hard code decision values 306. Forexample a transmission symbol 208 of “1” is converted to a bit 202 of“0” and a transmission symbol 208 of “−1” is converted to a bit 202 of“1”. The hard code decision value 306 at row one R1, column five C5 of“0” is also an error correcting code 206, i.e., parity code, for thehard code decision value set 308.

An error check is performed using the error correcting code 204 of thehard code decision value set 308. For example, the parity code “0” ofrow one R1, column five C5 (Figure C5) is used to determine if parity iseven. In this example, even parity was set originally for row R1, andthe parity check fails.

FIG. 9D is an illustration of adjusted measured signals 310, accordingto one embodiment. Particularly, in FIG. 9D, the measured signals 302 ofa measured signal set 304 (FIG. 9A) are adjusted based on the outcome ofthe error check of the hard code decision value set 308 (FIG. 9C). Theadjusted measured signals 310 are grouped into subsets, sometimesreferred to as adjusted measured signals set 312. The adjusted measuredsignal sets 312 correspond to the measured signal set 304 (FIG. 9A), tothe hard code decision value sets 308 (FIG. 9C), to the transmissionsymbol sets 210 (FIG. 8C), and to the bits sets 204 (FIG. 8B).

If the hard code decision value set 308 passes the error check, eachmeasured signal 302 of the corresponding measured signal set 304 isadjusted by a predetermined delta toward its corresponding nearestpossible measurement if no noise were present, e.g., to the transmissionsymbol 208 of (1, −1) nearest in value to the current measured signal.

If the hard code decision value set 308 fails the error check, eachmeasured signal 302 of the corresponding measured signal set 304 isadjusted by a predetermined delta away from its corresponding nearestpossible measurement if no noise were present, e.g., to the nearesttransmission symbol 208 of (1, −1), as shown in FIG. 9B. In thisexample, the hard code decision value set 308 of FIG. 9C failed theerror check. Each measured signal 302 of measured signal set 304 of rowone R1 is adjusted by a predetermined delta of 0.05 away from itsnearest possible measurement if no noise were present.

In several embodiments of the communications decoder, the predetermineddelta is determined by simulation. The predetermined delta can vary withthe iteration process and can be reduced or otherwise modified asconvergence is achieved. In this respect, “convergence” refers toconvergence of a particular measured signal on a single point duringiterative adjustments to the particular measured signal, thus theassociated parity errors begin to decrease. In this manner, accuracy ofthe decoded data increases.

For example, the predetermined delta is small enough to provide smallbut steady changes to a particular measured signal value until themeasured signal value converges to a point where its associated parityerrors begin to decrease.

In embodiments of the communications decoder, each measured signal hasat least two associated error correcting codes to provide multipleopportunities for adjustment during a single pass. For example, if themeasured signal sets are arranged in a two-dimensional geometry, eachmeasured signal has two associated error correcting codes. In athree-dimensional geometry, each measured signal has three associatederror checking codes.

The preceding steps are performed iteratively in sequence for eachmeasured signal set 304 of the encoded data 108 (FIG. 9A). Completion ofthe iterative sequence across all measured sets of the encoded data issometimes referred to as a “pass”. In a two-dimensional matrix, forexample, where the data are grouped by row and column, the precedingsteps are performed in sequence for each row and each column of thematrix to complete one pass.

Multiple passes can be performed to lower the probability of assignmentof measured signals to a transmission value associated with a bit thatdoes not correspond to the original bit. The multiple passes can beperformed until predetermined stopping condition(s) are met. Dependingon the delta, three or four passes can be sufficient to minimize theprobability of error. In this manner, the communications decoderutilizes error detection correcting codes and a simple, iterativeprocess to achieve highly accurate decoding results with minimaloverhead and minimal cost.

In one embodiment of the communications decoder, the predeterminedstopping condition includes convergence of the adjusted measured signalson their most likely transmitted value. In another embodiment, thepasses are stopped when no further changes occur in the hard codedecision values between passes. In still another embodiment, thepredetermined stopping condition can be a preset number of passes.Another predetermined stopping condition is an internal check thatindicates the encoded data has a high probability of being accuratelydecoded, e.g., a cyclic redundancy check (CRC) is performed on thedecoded data. Other predetermined stopping conditions are also possible.

Various embodiments of the communications decoder use error correctingcodes such as Hamming codes or Golay codes. Hamming codes and Golaycodes typically encode each bit set with multiple parity codes. In thismanner, an error check using the codes can identify a particular hardcode decision value in error, including a magnitude of directional driveof a signal measurement in error.

Thus, in various embodiments of the communications decoder using Hammingcodes or Golay codes, error check(s) are performed on each hard codedecision value set according to standard Hamming code or Golay codespractices. The additional information given by error correction codessuch as Hamming codes or Golay codes is used to drive the adjustedmeasurements of detected errors away from hard coded decision values andother bits toward hard coded decision values. The above-describedprocess is performed against each measured signal set until apredetermined stopping condition is met. Although the number of codesper set of encoded data greatly increases with the use of Hamming codesor Golay codes and the overhead associated with the error checksincreases, convergence occurs more quickly than with data encoded withsimple parity bits (one parity bit per bit set).

Various embodiments are associated with QAM modulation, wherein a groupof bits is associated with an I, Q coordinate pair. The above iterationsequence and multiple pass approach can still be applied. For example,the hard code decision value is associated with the closest desired I, Qpair to identify hard code decision values. The I, Q pair is modified tobe driven closer to (upon a passed error check) or further from (upon afailed error check) a nearest desired measurement point. Each bitassociated with an I, Q point drives that point as it be evaluated inthe above iteration sequence. The above process can be generalized tomultidimensional signal constellations, such as where QAM is used by twodifferent polarizations in microwave radio systems to create a fourdimensional received constellation point.

FIG. 10 is a flowchart of a method associated with decoding, accordingto one embodiment of the invention. Particularly, FIG. 10 includes aDETERMINE A NEAREST POSSIBLE MEASUREMENT FOR EACH MEASURED SIGNAL IN AMEASURED SIGNAL SET OF ENCODED DATA 402 operation. In the DETERMINE ANEAREST POSSIBLE MEASUREMENT FOR EACH MEASURED SIGNAL IN A MEASUREDSIGNAL SET OF ENCODED DATA 402 operation, a nearest possible measurementif no noise were present is associated with each measured signal in ameasured signal set, as previously discussed.

From the DETERMINE A NEAREST POSSIBLE MEASUREMENT FOR EACH MEASUREDSIGNAL IN A MEASURED SIGNAL SET OF ENCODED DATA 402 operation, flowmoves to a CONVERT EACH NEAREST POSSIBLE MEASUREMENT TO A HARD CODEDECISION VALUE 404 operation. In the CONVERT EACH NEAREST POSSIBLEMEASUREMENT TO A HARD CODE DECISION VALUE 404 operation, each nearestpossible measurement associated with each measured signal in a measuredsignal set is converted to a corresponding hard code decision value,e.g., bit 1 or 0, as previously discussed.

From the CONVERT EACH NEAREST POSSIBLE MEASUREMENT TO A HARD CODEDECISION VALUE 404 operation, flow moves to a PERFORM AN ERROR CHECK ONTHE HARD CODE DECISION VALUES 406 operation. In the PERFORM AN ERRORCHECK ON THE HARD CODE DECISION VALUES 406 operation, an error check isperformed on the hard code decision value set, as previously discussed.

From the PERFORM AN ERROR CHECK ON THE HARD CODE DECISION VALUES 406operation, flow moves to a PASS ERROR CHECK 408 operation. In the PASSERROR CHECK 408 operation, a determination is made if the hard codedecision value set passed the error check (a passed error check) orfailed the error check (a failed error check).

Upon the passed error check, flow moves to an ADJUST EACH MEASUREDSIGNAL TOWARD NEAREST POSSIBLE MEASUREMENT 410 operation. In the ADJUSTEACH MEASURED SIGNAL TOWARD NEAREST POSSIBLE MEASUREMENT 410 operation,each measured signal of the measured signal set is adjusted toward thenearest possible measurement, as previously discussed.

Upon the failed error check, flow moves to an ADJUST EACH MEASUREDSIGNAL AWAY FROM NEAREST POSSIBLE MEASUREMENT 412 operation. In theADJUST EACH MEASURED SIGNAL AWAY FROM NEAREST POSSIBLE MEASUREMENT 412operation, each measured signal of the measured signal set is adjustedaway from the nearest possible measurement, as previously discussed.

From either the ADJUST EACH MEASURED SIGNAL TOWARD NEAREST POSSIBLEMEASUREMENT 410 operation or the ADJUST EACH MEASURED SIGNAL AWAY FROMNEAREST POSSIBLE MEASUREMENT 412 operation, flow moves to a MOREMEASURED SIGNAL SETS 414 operation. In the MORE MEASURED SIGNAL SETS 414operation, a determination is made as to whether more measured signalsets remain to be processed in the sequence, as previously discussed.

Upon a determination that more measured signal sets remain, flow returnsto the DETERMINE A NEAREST POSSIBLE MEASUREMENT FOR EACH MEASURED SIGNALIN A MEASURED SIGNAL SET OF ENCODED DATA 402 operation.

Upon a determination that no more measured signals sets remain, flowmoves to a STOPPING CONDITION MET 416 operation. In the STOPPINGCONDITION MET 416 operation, a determination is made whether apredetermined stopping condition is met, as previously discussed.

Upon a determination that a stopping condition is not met, flow moves toa RESET TO FIRST MEASURED SIGNAL SET OF ENCODED DATA 418 operation.

From the RESET TO FIRST MEASURED SIGNAL SET OF ENCODED DATA 418operation, flow returns to the DETERMINE A NEAREST POSSIBLE MEASUREMENTFOR EACH MEASURED SIGNAL IN A MEASURED SIGNAL SET OF ENCODED DATA 402operation.

Upon a determination that a stopping condition is met, flow exits in anEXIT 420 operation. In this manner, the decoding method utilizes errorcorrecting codes and a simple, iterative process to achieve highlyaccurate decoding results.

FIG. 11 is a schematic of a communication environment 500, including acommunications decoder 508, according to one embodiment. Thecommunication environment 500 includes, for example, unencoded data 102,a transmitter 502, an encoder 504, encoded data 108, a receiver 506, thecommunications decoder 508, and decoded data 114. In variousembodiments, various components are partially or wholly integrated. Forexample, the encoder 504 can be partially or wholly integrated with thetransmitter 502. In another example, the communications decoder 508 canbe partially or wholly integrated with the receiver 506. In variousembodiments, the components can be implemented without co-integration.For example, the communications decoder 508 can be implemented as astand-alone component.

As previously discussed, the encoder 504 encodes unencoded data 102,such as a collection of bits. The encoder 504 encodes the unencoded data102 using error correcting codes (codes). The codes include paritycodes, Hamming codes, Golay codes, and other codes, as previouslydiscussed. In one embodiment, the encoder 504 encodes each set of bitsin the unencoded data 102. The encoder 504 or the transmitter 502transmits the encoded data 108. The encoded data can be transmitted astransmission symbols associated with analog signals, as previouslydiscussed. The receiver 506 receives and measures the signals associatedwith the encoded data 108, as previously discussed.

The communications decoder 508 rounds each set of measured signals tothe nearest possible measurement if no noise were present, e.g., to anearest transmission symbol. The communications decoder 508 converts theset of transmission symbols to a set of hard code decision values. Thecommunications decoder 508 performs an error check on the set of hardcode decision values, using an error correcting code associated with thehard code decision values. The communications decoder 508 adjusts eachmeasured signal in the set of measured signals based on an outcome ofthe error check of the set of hard code decision values. Thecommunications decoder 508 performs the foregoing steps across all ofthe sets of measured signals, in multiple passes, until a predeterminedstopping condition is met, resulting in decoded data 114. In thismanner, the decoder utilizes error correcting codes and a simple,iterative process to achieve highly accurate decoding results.

Multidimensional parity codes operate at 2 dB Eb/No (4 db Eb/No, 6 dbEb/No) when decoded in the described manner at an error rate of 10⁻⁵.These codes operate at a rate of R=0.5 (50% message bits; 50% paritycheck bits).

In addition, it will be appreciated that the various operations,processes, and methods disclosed herein can be embodied in amachine-readable medium and/or a machine accessible medium compatiblewith a data processing system (e.g., a computer system), and can beperformed in any order.

Forward Error Correction

In certain embodiments, the receiver is configured for use with an invivo transmitter that employs FEC (Forward Error Correction) to provideadditional gain to combat interference from other unwanted signals andnoise. The error correction is simple in the transmitter and receiver,and provides high coding gain. This functionality is achieved usingsingle parity check product codes and a novel SISO (Soft In Soft Out)iterative decoding algorithm.

The transmitter encodes the message by arranging it in rows and columns.Each row has an appended parity bit, and similarly each column has anappended parity bit. For example, a 100 bit message could be arranged ina 10 by 10 bit array. Parity bits would be added to create a final 11 by11 bit array that would then be transmitted on the channel using BPSK.For additional gain, additional dimensions could be used, such as threeif a cube were created to arrange the message and parity bits.

The receiver decodes the message by an iterative process to achieve highcoding gain. Each bit is sampled and saved in “soft” form. Assumingideal samples (i.e., hard decision points) are normalized to −1 and +1,received bits would come in a range between say, −2.0 and +2.0. A harddecision is made on all samples and parity checked. If a row or columnhas a parity error, the samples of that row or column are repulsed fromtheir corresponding hard decision point by a small delta. If the row orcolumn has no parity error, the samples of that row or column areattracted to their corresponding hard decision point by a small delta.Using a properly selected delta, based on expected channel SNR (Signalto Noise Ratio), ten iterations is usually sufficient to achieve an 8 to10 dB coding gain on AWGN (Additive White Gaussian Noise). This methodis easy to implement in stored program DSP or FPGA/ASIC logic. It alsocomes within one or two dB of the Shannon limit for forward errorcorrection given the particular coding rate.

Noise Canceling Receiver

In certain embodiments, signals from in vivo transmitter devices andnoise signals are maximized in different orientations. This scenariopermits using noise cancellation techniques to subtract the noise signalfrom the pill signal, to significantly enhance SNR (Signal to NoiseRatio). For example, it has been observed that skin probes placedlaterally (side to side) over the stomach pick-up greater pill signals,while probes placed longitudinally (head to toe) over the stomachpick-up greater external noise sources. The subtraction process usesadaptive digital filters on two sets of probes (one pair lateral, andone pair longitudinal) to greatly enhance SNR. The details of this noisecancellation algorithm are well known and often use Widrow's LMS (LeastMean Squares) adaptation algorithm, although many others can also beused. As such, in certain embodiments noise canceling technology isemployed to receive volume conduction sources that have low signalstrength and high noise backgrounds.

Systems

In certain embodiments, the signal receivers are part of a bodyassociated system or network of sensors, receivers, and optionally otherdevices, both internal and external, which provide a variety ofdifferent types of information that is ultimately collected andprocessed by a processor, such as an external processor, which then canprovide contextual data about a patient as output. For example thatsensor may be a member of an in-body network of devices which canprovide an output that includes data about pill ingestion, one or morephysiological sensed parameters, implantable device operation, etc., toan external collector of the data. The external collector, e.g., in theform of a health care network server, etc., of the data then combinesthis receiver provided data with additional relevant data about thepatient, e.g., weight, weather, medical record data, etc., and mayprocess this disparate data to provide highly specific and contextualpatient specific data.

Systems of the subject invention include, in certain embodiments, asignal receiver and one or more pharma-informatics enabled active agentcontaining compositions. The pharma-informatics enabled pharmaceuticalcomposition is an active agent-containing composition having anidentifier stably associated therewith. In certain embodiments, thecompositions are disrupted upon administration to a subject. As such, incertain embodiments, the compositions are physically broken, e.g.,dissolved, degraded, eroded, etc., following delivery to a body, e.g.,via ingestion, injection, etc. The compositions of these embodiments aredistinguished from devices that are configured to be ingested andsurvive transit through the gastrointestinal tract substantially, if notcompletely, intact. The compositions include an identifier and an activeagent/carrier component, where both of these components are present in apharmaceutically acceptable vehicle.

The identifiers of the compositions may vary depending on the particularembodiment and intended application of the composition so long as theyare activated (i.e., turned on) upon contact with a target physiologicallocation, e.g., stomach. As such, the identifier may be an identifierthat emits a signal when it contacts a target body (i.e., physiological)site. In addition or alternatively, the identifier may be an identifierthat emits a signal when interrogated after it has been activated. Theidentifier may be any component or device that is capable of providing adetectable signal following activation, e.g., upon contact with thetarget site. In certain embodiments, the identifier emits a signal oncethe composition comes into contact with a physiological target site,e.g., as summarized above. For example, a patient may ingest a pillthat, upon contact with the stomach fluids, generates a detectablesignal.

The compositions include an active agent/carrier component. By “activeagent/carrier component” is meant a composition, which may be a solid orfluid (e.g., liquid), which has an amount of active agent, e.g., adosage, present in a pharmaceutically acceptable carrier. The activeagent/carrier component may be referred to as a “dosage formulation.”

“Active agent” includes any compound or mixture of compounds whichproduces a physiological result, e.g., a beneficial or useful result,upon contact with a living organism, e.g., a mammal, such as a human.Active agents are distinguishable from such components as vehicles,carriers, diluents, lubricants, binders and other formulating aids, andencapsulating or otherwise protective components. The active agent maybe any molecule, as well as binding portion or fragment thereof, that iscapable of modulating a biological process in a living subject. Incertain embodiments, the active agent may be a substance used in thediagnosis, treatment, or prevention of a disease or as a component of amedication. In certain embodiments, the active agent may be a chemicalsubstance, such as a narcotic or hallucinogen, which affects the centralnervous system and causes changes in behavior.

The active agent (i.e., drug) is capable of interacting with a target ina living subject. The target may be a number of different types ofnaturally occurring structures, where targets of interest include bothintracellular and extracellular targets. Such targets may be proteins,phospholipids, nucleic acids and the like, where proteins are ofparticular interest. Specific proteinaceous targets of interest include,without limitation, enzymes, e.g. kinases, phosphatases, reductases,cyclooxygenases, proteases and the like, targets comprising domainsinvolved in protein-protein interactions, such as the SH2, SH3, PTB andPDZ domains, structural proteins, e.g. actin, tubulin, etc., membranereceptors, immunoglobulins, e.g. IgE, cell adhesion receptors, such asintegrins, etc, ion channels, transmembrane pumps, transcriptionfactors, signaling proteins, and the like.

The active agent (i.e., drug) may include one or more functional groupsnecessary for structural interaction with the target, e.g., groupsnecessary for hydrophobic, hydrophilic, electrostatic or even covalentinteractions, depending on the particular drug and its intended target.Where the target is a protein, the drug moiety may include functionalgroups necessary for structural interaction with proteins, such ashydrogen bonding, hydrophobic-hydrophobic interactions, electrostaticinteractions, etc., and may include at least an amine, amide,sulfhydryl, carbonyl, hydroxyl or carboxyl group, such as at least twoof the functional chemical groups.

Drugs of interest may include cyclical carbon or heterocyclic structuresand/or aromatic or polyaromatic structures substituted with one or moreof the above functional groups. Also of interest as drug moieties arestructures found among biomolecules, including peptides, saccharides,fatty acids, steroids, purines, pyrimidines, derivatives, structuralanalogs or combinations thereof. Such compounds may be screened toidentify those of interest, where a variety of different screeningprotocols are known in the art.

The drugs may be derived from a naturally occurring or syntheticcompound that may be obtained from a wide variety of sources, includinglibraries of synthetic or natural compounds. For example, numerous meansare available for random and directed synthesis of a wide variety oforganic compounds and biomolecules, including the preparation ofrandomized oligonucleotides and oligopeptides. Alternatively, librariesof natural compounds in the form of bacterial, fungal, plant and animalextracts are available or readily produced. Additionally, natural orsynthetically produced libraries and compounds are readily modifiedthrough conventional chemical, physical and biochemical means, and maybe used to produce combinatorial libraries. Known pharmacological agentsmay be subjected to directed or random chemical modifications, such asacylation, alkylation, esterification, amidification, etc. to producestructural analogs.

As such, the drug may be obtained from a library of naturally occurringor synthetic molecules, including a library of compounds producedthrough combinatorial means, i.e., a compound diversity combinatoriallibrary. When obtained from such libraries, the drug moiety employedwill have demonstrated some desirable activity in an appropriatescreening assay for the activity. Combinatorial libraries, as well asmethods for producing and screening such libraries, are known in the artand described in: U.S. Pat. Nos. 5,741,713; 5,734,018; 5,731,423;5,721,099; 5,708,153; 5,698,673; 5,688,997; 5,688,696; 5,684,711;5,641,862; 5,639,603; 5,593,853; 5,574,656; 5,571,698; 5,565,324;5,549,974; 5,545,568; 5,541,061; 5,525,735; 5,463,564; 5,440,016;5,438,119; 5,223,409, the disclosures of which are herein incorporatedby reference.

Broad categories of active agents of interest include, but are notlimited to: cardiovascular agents; pain-relief agents, e.g., analgesics,anesthetics, anti-inflammatory agents, etc.; nerve-acting agents;chemotherapeutic (e.g., anti-neoplastic) agents; etc.

As summarized above, the compositions of the invention further include apharmaceutically acceptable vehicle (i.e., carrier). Common carriers andexcipients, such as corn starch or gelatin, lactose, dextrose, sucrose,microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate,sodium chloride, and alginic acid are of interest. Disintegratorscommonly used in the formulations of the invention includecroscarmellose, microcrystalline cellulose, corn starch, sodium starchglycolate and alginic acid.

Further details about embodiments of pharma-informatics enabledpharmaceutical compositions may be found in pending PCT applicationPCT/US2006/16370 titled “Pharma-Informatics System” and filed on Apr.28, 2006; as well as U.S. Provisional Application Ser. No. 60/807,060titled “Acoustic Pharma-Informatics System” filed on Jul. 11, 2006;60/862,925 titled “Controlled Activation Pharma-Informatics System,”filed on Oct. 25, 2006; and 60/866,581 titled “In-Vivo TransmissionDecoder,” filed on Nov. 21, 2006; the disclosures of which are hereinincorporated by reference.

In certain embodiments the systems include an external device which isdistinct from the receiver (which may be implanted or topically appliedin certain embodiments), where this external device provides a number offunctionalities. Such an apparatus can include the capacity to providefeedback and appropriate clinical regulation to the patient. Such adevice can take any of a number of forms. By example, the device can beconfigured to sit on the bed next to the patient, e.g., a bedsidemonitor. Other formats include, but are not limited to, PDAs, smartphones, home computers, etc. The device can read out the informationdescribed in more detail in other sections of the subject patentapplication, both from pharmaceutical ingestion reporting and fromphysiological sensing devices, such as is produced internally by apacemaker device or a dedicated implant for detection of the pill. Thepurpose of the external apparatus is to get the data out of the patientand into an external device. One feature of the external apparatus isits ability to provide pharmacologic and physiologic information in aform that can be transmitted through a transmission medium, such as atelephone line, to a remote location such as a clinician or to a centralmonitoring agency.

Systems of the invention enable a dynamic feedback and treatment loop oftracking medication timing and levels, measuring the response totherapy, and recommending altered dosing based on the physiology andmolecular profiles of individual patients. For example, a symptomaticheart failure patient takes multiple drugs daily, primarily with thegoal of reducing the heart's workload and improving patient quality oflife. Mainstays of therapy include angiotensin converting enzyme (ACE)inhibitors, β-blockers and diuretics. For pharmaceutical therapy to beeffective, it is vital that patients adhere to their prescribed regimen,taking the required dose at the appropriate time. Multiple studies inthe clinical literature demonstrate that more than 50% of Class II andIII heart failure patients are not receiving guideline-recommendedtherapy, and, of those who are titrated appropriately, only 40-60%adhere to the regimen. With the subject systems, heart failure patientscan be monitored for patient adherence to therapy, and adherenceperformance can be linked to key physiologic measurements, to facilitatethe optimization of therapy by physicians.

In certain embodiments, the systems of the invention may be employed toobtain an aggregate of information that includes sensor data andadministration data. For example, one can combine the heart rate, therespiration rate, multi-axis acceleration data, something about thefluid status, and something about temperature, and derive indices thatwill inform about the total activity of the subject, that can be used togenerate a physiological index, such as an activity index. For instance,when there is a rise in temperature, heart rate goes up a bit, andrespiration speeds up, which may be employed as an indication that theperson is being active. By calibrating this, the amount of calories theperson is burning at that instant could be determined. In anotherexample, a particular rhythmic set of pulses or multi-axis accelerationdata can indicate that a person is walking up a set of stairs, and fromthat one can infer how much energy they are using. In anotherembodiment, body fat measurement (e.g. from impedance data) could becombined with an activity index generated from a combination of measuredbiomarkers to generate a physiological index useful for management of aweight loss or cardiovascular health program. This information can becombined with cardiac performance indicators to get a good picture ofoverall health, which can be combined with pharmaceutical therapyadministration data. In another embodiment, one might find for examplethat a particular pharmaceutical correlates with a small increase inbody temperature, or a change in the electrocardiogram. One can developa pharmacodynamic model for the metabolism of the drug, and use theinformation from the receiver to essentially fit the free parameters inthat model to give much more accurate estimation of the levels actuallypresent in the serum of the subject. This information could be fed backto dosing regimes. In another embodiment, one can combine informationfrom a sensor that measures uterine contractions (e.g. with a straingauge) and that also monitors fetal heart rate, for use as a high-riskpregnancy monitor.

In certain embodiments, the subject specific information that iscollected using the systems of the invention may be transmitted to alocation where it is combined with data from one or more additionalindividuals to provide a collection of data which is a composite of datacollected from 2 or more, e.g., 5 or more, 10 or more, 25 or more, 50 ormore, 100 or more, 1000 or more, etc., individuals. The composite datacan then be manipulated, e.g., categorized according to differentcriteria, and made available to one or more different types of groups,e.g., patient groups, health care practitioner groups, etc., where themanipulation of data may be such as to limit the access of any givengroup to the type of data that group can access. For example, data canbe collected from 100 different individuals that are suffering from thesame condition and taking the same medication. The data can be processedand employed to develop easy to follow displays regarding patientcompliance with a pharmaceutical dosage regimen and general health.Patient members of the group can access this information and see howtheir compliance matches with other patient members of the group, andwhether they are enjoying the benefits that others are experiencing. Inyet another embodiment, doctors can also be granted access to amanipulation of the composite data to see how their patients arematching up with patients of other doctors, and obtain usefulinformation on how real patients respond to a given therapeutictreatment regiment. Additional functionalities can be provided to thegroups given access to the composite data, where such functionalitiesmay include, but are not limited to: ability to annotate data, chatfunctionalities, security privileges, etc.

Computer Readable Media & Programming

In certain embodiments, the system further includes an element forstoring data, i.e., a data storage element, where this element ispresent on an external device, such as a bedside monitor, PDA, smartphone, etc. Typically, the data storage element is a computer readablemedium. The term “computer readable medium” as used herein refers to anystorage or transmission medium that participates in providinginstructions and/or data to a computer for execution and/or processing.Examples of storage media include floppy disks, magnetic tape, CD-ROM, ahard disk drive, a ROM or integrated circuit, a magneto-optical disk, ora computer readable card such as a PCMCIA card and the like, whether ornot such devices are internal or external to the computer. A filecontaining information may be “stored” on computer readable medium,where “storing” means recording information such that it is accessibleand retrievable at a later date by a computer. With respect to computerreadable media, “permanent memory” refers to memory that is permanent.Permanent memory is not erased by termination of the electrical supplyto a computer or processor. Computer hard-drive ROM (i.e. ROM not usedas virtual memory), CD-ROM, floppy disk and DVD are all examples ofpermanent memory. Random Access Memory (RAM) is an example ofnon-permanent memory. A file in permanent memory may be editable andre-writable.

The invention also provides computer executable instructions (i.e.,programming) for performing the above methods. The computer executableinstructions are present on a computer readable medium. Accordingly, theinvention provides a computer readable medium containing programming foruse in detecting and processing a signal generated by a composition ofthe invention, e.g., as reviewed above.

As such, in certain embodiments the systems include one or more of: adata storage element, a data processing element, a data display element,data transmission element, a notification mechanism, and a userinterface. These additional elements may be incorporated into thereceiver and/or present on an external device, e.g., a device configuredfor processing data and making decisions, forwarding data to a remotelocation which provides such activities, etc.

The above described systems are reviewed in terms of communicationbetween an identifier on a pharmaceutical composition and a receiver.However, the systems are not so limited. In a broader sense, the systemsare composed of two or more different modules that communicate with eachother, e.g., using the transmitter/receiver functionalities as reviewedabove, e.g., using the monopole transmitter (e.g., antenna) structuresas described above. As such, the above identifier elements may beincorporated into any of a plurality of different devices, e.g., toprovide a communications system between two self-powered devices in thebody, where the self-powered devices may be sensors, data receivers andstorage elements, effectors, etc. In an exemplary system, one of thesedevices may be a sensor and the other may be a communication hub forcommunication to the outside world. This inventive embodiment may take anumber of forms. There can be many sensors, many senders and onereceiver. They can be transceivers so both of these can take turnssending and receiving according to known communication protocols. Incertain embodiments, the means of communication between the two or moreindividual devices is the mono polar system, e.g., as described above.In these embodiments, each of these senders may be configured to taketurns sending a high frequency signal into the body using a monopolepulling charge into and out of the body which is a large capacitor and aconductor. The receiver, a monopole receiver is detecting at thatfrequency the charge going into and out of the body and decoding anencrypted signal such as an amplitude modulated signal or frequencymodulated signal. This embodiment of the present invention has broaduses. For example, multiple sensors can be placed and implanted onvarious parts of the body that measure position or acceleration. Withouthaving wires connecting to a central hub, they can communicate thatinformation through a communication medium.

Receiver Fabrication

As reviewed above, in certain embodiments of interest, the receiverelement includes a semiconductor support component. Any of a variety ofdifferent protocols may be employed in manufacturing the receiverstructures and components thereof. For example, molding, deposition andmaterial removal, e.g., planar processing techniques, such asMicro-Electro-Mechanical Systems (MEMS) fabrication techniques,including surface micromachining and bulk micromachining techniques, maybe employed. Deposition techniques that may be employed in certainembodiments of fabricating the structures include, but are not limitedto: electroplating, cathodic arc deposition, plasma spray, sputtering,e-beam evaporation, physical vapor deposition, chemical vapordeposition, plasma enhanced chemical vapor deposition, etc. Materialremoval techniques included, but are not limited to: reactive ionetching, anisotropic chemical etching, isotropic chemical etching,planarization, e.g., via chemical mechanical polishing, laser ablation,electronic discharge machining (EDM), etc. Also of interest arelithographic protocols. Of interest in certain embodiments is the use ofplanar processing protocols, in which structures are built up and/orremoved from a surface or surfaces of an initially planar substrateusing a variety of different material removal and deposition protocolsapplied to the substrate in a sequential manner. Illustrativefabrication methods of interest are described in greater detail incopending PCT application serial no. PCT/US2006/016370; the disclosureof which is herein incorporated by reference.

In certain embodiments, off-the-shelf components may be employed tofabricate the receivers. For example, an off-the-shelf instrumentationamplifier for the input amp may be employed, e.g., in bare die form.Custom logic, either in an FPGA or in an ASIC, that handles thedemodulator, the memory, the microprocessor functions, and all theinterface functions may be used. The transmitter may be an off-the-shelfchip, e.g., made by Zarlink, in the mixed communication band, which isapproved for medical implants. The clock may be a stand-alone clock, orthe device may have a microprocessor that has a clock built in.

Methods

In methods of invention, a signal is first transmitted from an in vivotransmitter, such as a pharma-informatics enabled composition. Thetransmitted signal is then received by the receiver, where it may bestored to a memory, retransmitted to another receiver, output to a user,e.g., either directly or via a third device, e.g., an external PDA, etc.

In the methods of the subject invention in which the in vivo transmitteris a pharma-informatics enabled composition, an effective amount of acomposition of the invention is administered to a subject in need of theactive agent present in the composition, where “effective amount” meansa dosage sufficient to produce the desired result, e.g. an improvementin a disease condition or the symptoms associated therewith, theaccomplishment of a desired physiological change, etc. The amount thatis administered may also be viewed as a therapeutically effectiveamount. A “therapeutically effective amount” means the amount that, whenadministered to a subject for treating a disease, is sufficient toeffect treatment for that disease.

The composition may be administered to the subject using any convenientmeans capable of producing the desired result, where the administrationroute depends, at least in part, on the particular format of thecomposition, e.g., as reviewed above. As reviewed above, thecompositions can be formatted into a variety of formulations fortherapeutic administration, including but not limited to solid, semisolid or liquid, such as tablets, capsules, powders, granules,ointments, solutions, suppositories and injections. As such,administration of the compositions can be achieved in various ways,including, but not limited to: oral, buccal, rectal, parenteral,intraperitoneal, intradermal, transdermal, intracheal, etc.,administration. In pharmaceutical dosage forms, a given composition maybe administered alone or in combination with other pharmaceuticallyactive compounds, e.g., which may also be compositions having signalgeneration elements stably associated therewith.

The subject methods find use in the treatment of a variety of differentconditions, including disease conditions. The specific diseaseconditions treatable by with the subject compositions are as varied asthe types of active agents that can be present in the subjectcompositions. Thus, disease conditions include, but are not limited to:cardiovascular diseases, cellular proliferative diseases, such asneoplastic diseases, autoimmune diseases, hormonal abnormality diseases,infectious diseases, pain management, and the like.

By treatment is meant at least an amelioration of the symptomsassociated with the disease condition afflicting the subject, whereamelioration is used in a broad sense to refer to at least a reductionin the magnitude of a parameter, e.g. symptom, associated with thepathological condition being treated. As such, treatment also includessituations where the pathological condition, or at least symptomsassociated therewith, are completely inhibited, e.g. prevented fromhappening, or stopped, e.g. terminated, such that the subject no longersuffers from the pathological condition, or at least the symptoms thatcharacterize the pathological condition. Accordingly, “treating” or“treatment” of a disease includes preventing the disease from occurringin an animal that may be predisposed to the disease but does not yetexperience or exhibit symptoms of the disease (prophylactic treatment),inhibiting the disease (slowing or arresting its development), providingrelief from the symptoms or side-effects of the disease (includingpalliative treatment), and relieving the disease (causing regression ofthe disease). For the purposes of this invention, a “disease” includespain.

A variety of subjects are treatable according to the present methods.Generally such subjects are “mammals” or “mammalian,” where these termsare used broadly to describe organisms which are within the classmammalia, including the orders carnivore (e.g., dogs and cats), rodentia(e.g., mice, guinea pigs, and rats), and primates (e.g., humans,chimpanzees, and monkeys). In representative embodiments, the subjectswill be humans.

In certain embodiments, the subject methods, as described above, aremethods of managing a disease condition, e.g., over an extended periodof time, such as 1 week or longer, 1 month or longer, 6 months orlonger, 1 year or longer, 2 years or longer, 5 years or longer, etc. Thesubject methods may be employed in conjunction with one or moreadditional disease management protocols, e.g., electrostimulation basedprotocols in cardiovascular disease management, such as pacingprotocols, cardiac resynchronization protocols, etc; lifestyle, such adiet and/or exercise regimens for a variety of different diseaseconditions; etc.

In certain embodiments, the methods include modulating a therapeuticregimen based data obtained from the compositions. For example, data maybe obtained which includes information about patient compliance with aprescribed therapeutic regimen. This data, with or without additionalphysiological data, e.g., obtained using one or more sensors, such asthe sensor devices described above, may be employed, e.g., withappropriate decision tools as desired, to make determinations of whethera given treatment regimen should be maintained or modified in some way,e.g., by modification of a medication regimen and/or implant activityregimen. As such, methods of invention include methods in which atherapeutic regimen is modified based on signals obtained from thecomposition(s).

In certain embodiments, also provided are methods of determining thehistory of a composition of the invention, where the compositionincludes an active agent, an identifier element and a pharmaceuticallyacceptable carrier. In certain embodiments where the identifier emits asignal in response to an interrogation, the identifier is interrogate,e.g., by a wand or other suitable interrogation device, to obtain asignal. The obtained signal is then employed to determine historicalinformation about the composition, e.g., source, chain of custody, etc.

In yet other embodiments where the identifier is one that survivesdigestion, the methods generally include obtaining the signal generationelement of the composition, e.g., by retrieving it from a subject thathas ingested the composition, and then determining the history of thecomposition from obtained signal generation element. For example, wherethe signal generation element includes an engraved identifier, e.g.,barcode or other type of identifier, the engraved identifier may beretrieved from a subject that has ingested the composition and then readto identify at least some aspect of the history of the composition, suchas last known purchaser, additional purchasers in the chain of custodyof the composition, manufacturer, handling history, etc. In certainembodiments, this determining step may include accessing a database oranalogous compilation of stored history for the composition.

Utility

Medical embodiments of the present invention provide the clinician animportant new tool in their therapeutic armamentarium: automaticdetection and identification of pharmaceutical agents actually deliveredinto the body. The applications of this new information device andsystem are multi-fold. Applications include, but are not limited to: (1)monitoring patient compliance with prescribed therapeutic regimens; (2)tailoring therapeutic regimens based on patient compliance; (3)monitoring patient compliance in clinical trials; (4) monitoring usageof controlled substances; and the like. Each of these differentillustrative applications is reviewed in greater detail below incopending PCT Application Serial No. PCT/US2006/016370; the disclosureof which is herein incorporated by reference. Additional applications inwhich the subject receivers find use include, but are not limited to:U.S. provisional Application Ser. No. 60/887,780 titled “SignalReceivers For Pharma-Informatics Systems,” and filed on Feb. 1, 2007;60/956,694 titled “Personal Health Signal Receivers,” and filed on Aug.18, 2007 and 60/949,223 titled “Ingestible Event Marker,” and filed onJul. 11, 2007, the disclosures of which applications are incorporatedherein by reference.

Kits

Also provided are kits for practicing the subject methods. Kits mayinclude one or more receivers of the invention, as described above. Inaddition, the kits may include one or more dosage compositions, e.g.,pharma-informatics enabled dosage compositions. The dosage amount of theone or more pharmacological agents provided in a kit may be sufficientfor a single application or for multiple applications. Accordingly, incertain embodiments of the subject kits a single dosage amount of apharmacological agent is present and in certain other embodimentsmultiple dosage amounts of a pharmacological agent may be present in akit. In those embodiments having multiple dosage amounts ofpharmacological agent, such may be packaged in a single container, e.g.,a single tube, bottle, vial, and the like, or one or more dosage amountsmay be individually packaged such that certain kits may have more thanone container of a pharmacological agent.

Suitable means for delivering one or more pharmacological agents to asubject may also be provided in a subject kit. The particular deliverymeans provided in a kit is dictated by the particular pharmacologicalagent employed, as describe above, e.g., the particular form of theagent such as whether the pharmacological agent is formulated intopreparations in solid, semi solid, liquid or gaseous forms, such astablets, capsules, powders, granules, ointments, solutions,suppositories, injections, inhalants and aerosols, and the like, and theparticular mode of administration of the agent, e.g., whether oral,buccal, rectal, parenteral, intraperitoneal, intradermal, transdermal,intracheal, etc. Accordingly, certain systems may include a suppositoryapplicator, syringe, I.V. bag and tubing, electrode, etc.

In certain embodiments, the kits may also include an external monitordevice, e.g., as described above, which may provide for communicationwith a remote location, e.g., a doctor's office, a central facilityetc., which obtains and processes data obtained about the usage of thecomposition.

In certain embodiments, the kits may include a smart parenteral deliverysystem that provides specific identification and detection of parenteralbeneficial agents or beneficial agents taken into the body through othermethods, for example, through the use of a syringe, inhaler, or otherdevice that administers medicine, such as described in copendingapplication Ser. No. 60/819,750; the disclosure of which is hereinincorporated by reference.

The subject kits may also include instructions for how to practice thesubject methods using the components of the kit. The instructions may berecorded on a suitable recording medium or substrate. For example, theinstructions may be printed on a substrate, such as paper or plastic,etc. As such, the instructions may be present in the kits as a packageinsert, in the labeling of the container of the kit or componentsthereof (i.e., associated with the packaging or sub-packaging) etc. Inother embodiments, the instructions are present as an electronic storagedata file present on a suitable computer readable storage medium, e.g.CD-ROM, diskette, etc. In yet other embodiments, the actual instructionsare not present in the kit, but means for obtaining the instructionsfrom a remote source, e.g. via the internet, are provided. An example ofthis embodiment is a kit that includes a web address where theinstructions can be viewed and/or from which the instructions can bedownloaded. As with the instructions, this means for obtaining theinstructions is recorded on a suitable substrate.

Some or all components of the subject kits may be packaged in suitablepackaging to maintain sterility. In many embodiments of the subjectkits, the components of the kit are packaged in a kit containmentelement to make a single, easily handled unit, where the kit containmentelement, e.g., box or analogous structure, may or may not be an airtightcontainer, e.g., to further preserve the sterility of some or all of thecomponents of the kit.

It is to be understood that this invention is not limited to particularembodiments described, as such may vary. It is also to be understoodthat the terminology used herein is for the purpose of describingparticular embodiments only, and is not intended to be limiting, sincethe scope of the present invention will be limited only by the appendedclaims.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimit of that range and any other stated or intervening value in thatstated range, is encompassed within the invention. The upper and lowerlimits of these smaller ranges may independently be included in thesmaller ranges and are also encompassed within the invention, subject toany specifically excluded limit in the stated range. Where the statedrange includes one or both of the limits, ranges excluding either orboth of those included limits are also included in the invention.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can also beused in the practice or testing of the present invention, representativeillustrative methods and materials are now described.

All publications and patents cited in this specification are hereinincorporated by reference as if each individual publication or patentwere specifically and individually indicated to be incorporated byreference and are incorporated herein by reference to disclose anddescribe the methods and/or materials in connection with which thepublications are cited. The citation of any publication is for itsdisclosure prior to the filing date and should not be construed as anadmission that the present invention is not entitled to antedate suchpublication by virtue of prior invention. Further, the dates ofpublication provided may be different from the actual publication dateswhich may need to be independently confirmed.

It is noted that, as used herein and in the appended claims, thesingular forms “a”, “an”, and “the” include plural referents unless thecontext clearly dictates otherwise. It is further noted that the claimsmay be drafted to exclude any optional element. As such, this statementis intended to serve as antecedent basis for use of such exclusiveterminology as “solely,” “only” and the like in connection with therecitation of claim elements, or use of a “negative” limitation.

As will be apparent to those of skill in the art upon reading thisdisclosure, each of the individual embodiments described and illustratedherein has discrete components and features which may be readilyseparated from or combined with the features of any of the other severalembodiments without departing from the scope or spirit of the presentinvention. Any recited method can be carried out in the order of eventsrecited or in any other order which is logically possible.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is readily apparent to those of ordinary skill in theart in light of the teachings of this invention that certain changes andmodifications may be made thereto without departing from the spirit orscope of the appended claims.

Accordingly, the preceding merely illustrates the principles of theinvention. It will be appreciated that those skilled in the art will beable to devise various arrangements which, although not explicitlydescribed or shown herein, embody the principles of the invention andare included within its spirit and scope. Furthermore, all examples andconditional language recited herein are principally intended to aid thereader in understanding the principles of the invention and the conceptscontributed by the inventors to furthering the art, and are to beconstrued as being without limitation to such specifically recitedexamples and conditions. Moreover, all statements herein recitingprinciples, aspects, and embodiments of the invention as well asspecific examples thereof, are intended to encompass both structural andfunctional equivalents thereof. Additionally, it is intended that suchequivalents include both currently known equivalents and equivalentsdeveloped in the future, i.e., any elements developed that perform thesame function, regardless of structure. The scope of the presentinvention, therefore, is not intended to be limited to the exemplaryembodiments shown and described herein. Rather, the scope and spirit ofpresent invention is embodied by the appended claims.

1. A signal receiver comprising: (a) an automatic gain controllerconfigured to receive an encoded signal from an in vivo transmitter in alow signal to noise ratio (SNR) environment and to actively adjust tovariations in the frequency and power of the incoming signal; (b) ademodulator configured to receive the actively adjusted encoded signalfrom the automatic gain controller and reconstruct the encoded signallocked in frequency and phase to the received encoded signal andapproximate the original un-encoded signal; (c) a symbol recoverycomponent configured to receive the reconstructed encoded signal anddetermine the signal clock of the reconstructed encoded signal, identifythe start sequence in the reconstructed encoded signal, determine thephase of the reconstructed encoded signal, and produce a decoded signalwith substantially no error; (d) wherein the signal receiver is sized tobe stably associated with a living subject in a manner that does notsubstantially impact movement of the living subject.
 2. The signalreceiver according to claim 1, wherein the signal receiver has a highcoding gain.
 3. The signal receiver according to claim 2, wherein thesignal receiver has a coding gain ranging from 6 dB to 12 dB.
 4. Thesignal receiver according to claim 3, wherein the signal receiver has acoding gain ranging from 8 dB to 10 dB.
 5. The signal receiver accordingto claim 4, wherein the signal receiver has a coding gain of 9 dB. 6.The signal receiver according to claim 1, wherein the SNR is 7.7 dB orless.
 7. The signal receiver according to claim 1, wherein the receiveris configured to decode the encoded signal with 10% error or less. 8.The signal receiver according to claim 1, wherein the encoded signal istransmitted conductively.
 9. The signal receiver according to claim 1,wherein the encoded signal is a signal that has been modulated usingfrequency shift keying (FSK), on off keying (OOK), amplitude modulation(AM), quadrature amplitude modulation (QAM), or binary phase shiftkeying (BPSK).
 10. The signal receiver according to claim 9, wherein theencoded signal is a signal that has been modulated using binary phaseshift keying (BPSK).
 11. The signal receiver according to claim 1,wherein the receiver comprises a coherent demodulator functional block.12. The signal receiver according to claim 11, wherein the receivercomprises a Costas loop demodulating functional block.
 13. The signalreceiver according to claim 1, wherein the receiver further comprises anactively adjustable rate sampler for an incoming signal.
 14. The signalreceiver according claim 1, further comprising a decoder blockconfigured to translate measured signals into data having a lowprobability of error.
 15. The signal receiver according to claim 14,wherein the decoder block is configured to: (a) convert measured signalsto hard code decision values; (b) perform an error check on the hardcode decision values to assess a likelihood of errors associated withthe hard code decision values; and (c) based on results of the errorcheck, adjust the measured signals toward or away from a measurementpoint.
 16. The signal receiver according to claim 1, wherein the livingsubject is a human subject.
 17. The signal receiver according to claim1, wherein the signal receiver has a volume that is about 5 cm³ or less.18. The signal receiver according to claim 3, wherein the signalreceiver has a chip size limit ranging from 10 mm² to 2 cm².
 19. Thesignal receiver according to claim 4, wherein the signal receiver has avolume that is about 1 cm³ or less.
 20. The signal receiver according toclaim 1, wherein the signal receiver is configured to be contacted withan external location of the human subject.
 21. The signal receiveraccording to claim 1, wherein the signal receiver has a topical patchconfiguration.
 22. The signal receiver according to claim 1, wherein thesignal receiver is an implantable signal receiver that is configured tobe implanted inside of the living subject.
 23. The signal receiveraccording to claim 1, wherein the signal receiver is configured toretransmit data of a received signal to a location external to theliving subject.
 24. The signal receiver according to claim 1, furthercomprising a power generation element.
 25. The signal receiver accordingto claim 1, further comprising a data storage element.
 26. A method oftransmitting data from an in vivo transmitter to a body associatedreceiver sized to be stably associated with a living subject in a mannerthat does not substantially impact movement of the living subject, themethod comprising: (a) transmitting a modulated encoded data signal fromthe in vivo transmitter to the body associated receiver; and (b)receiving the modulated encoded data signal at the body associatedreceiver in accordance with the following method: (i) receiving themodulated encoded signal in a low signal to noise ratio (SNR)environment and to actively adjust to variations in the frequency andpower of the incoming signal; i. (ii) demodulating the actively adjustedencoded signal and reconstructing the encoded signal locked in frequencyand phase to the incoming encoded signal and approximating the originalun-encoded signal; ii. (iii) receiving the reconstructed encoded signaland determining the signal clock of the reconstructed encoded signal,identifying the start sequence in the reconstructed encoded signal,determining the phase of the reconstructed encoded signal, and producinga decoded signal with substantially no error.
 27. The method accordingto claim 26, comprising actively adjusting the sampling rate of theincoming signal using an adjustable rate sampler.
 28. The methodaccording to claim 26, comprising translating, by the decoder block,measured signals into data having a low probability of error.
 29. Themethod according to claim 26, comprising, by the decoder block of thesignal receiver: (a) converting measured signals to hard code decisionvalues; (b) performing an error check on the hard code decision valuesand assessing a likelihood of errors associated with the hard codedecision values; and (c) based on results of the error check, adjustingthe measured signals toward or away from a measurement point.
 30. Asystem comprising: (a) a signal receiver according to claim 1; and (b)an in vivo signal transmitter.